Pyrazole derivatives

ABSTRACT

This invention relates to pyrazole derivatives of formula (I) 
                         
or pharmaceutically acceptable salts, solvates or derivative thereofs, wherein R1 to R4 are defined in the description, and to processes for the preparation thereof, intermediates used in their preparation of, compositions containing them and the uses of such derivatives.
 
     The compounds of the present invention bind to the enzyme reverse transcriptase and are modulators, especially inhibitors thereof. As such the compounds of the present invention are useful in the treatment of a variety of disorders including those in which the inhibition of reverse transcriptase is implicated. Disorders of interest include those caused by Human Immunodeficiency Virus (HIV) and genetically related retroviruses, such as Acquired Immune Deficiency Syndrome (AIDS).

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. Ser. No.11,157,340, filed Jun. 20, 2005 now U.S. Pat. No. 7,435,728, which is adivisional of U.S. Ser. No. 10/118,512, filed Apr. 5, 2002 now U.S. Pat.No. 7,109,228, which claims the benefit of priority to U.S. ProvisionalPatent Application 60/346,727, filed Jan. 7, 2002, and also claims thebenefit of priority to U.S. Provisional Patent Application 60/289,570,filed May 8, 2001, and also claims the benefit of priority to UnitedKingdom Application Number 0127426.5, filed Nov. 15, 2001, and alsoclaims the benefit of priority to United Kingdom Application Number0108999.4, filed Apr. 10, 2001.

This invention relates to pyrazole derivatives and to processes for thepreparation thereof, intermediates used in their preparation of,compositions containing them and the uses of such derivatives.

The compounds of the present invention bind to the enzyme reversetranscriptase and are modulators, especially inhibitors thereof. Reversetranscriptase is implicated in the infectious lifecycle of HIV, andcompounds which interfere with the function of this enzyme have shownutility in the treatment of conditions including AIDS. There is aconstant need to provide new and better modulators, especiallyinhibitors, of HIV reverse transcriptase since the virus is able tomutate, becoming resistant to the effects of know modulators.

The compounds of the present invention are useful in the treatment of avariety of disorders including, those in which the inhibition of reversetranscriptase is implicated. Disorders of interest include those causedby Human Immunodeficiency Virus (HIV) and genetically relatedretroviruses, such as Acquired Immune Deficiency Syndrome (AIDS).

European patent application EP 0 786 455 A1 discloses a class ofimidazole compounds which inhibit the growth of HIV. A class ofN-phenylpyrazoles which act as reverse transcriptase inhibitors aredisclosed in J. Med. Chem., 2000, 43, 1034. Antiviral activity isascribed to a class of N-(hydroxyethyl)pyrazole derivatives in U.S. Pat.No. 3,303,200.

According to the present invention there is provided a compound of theformula

or a pharmaceutically acceptable salt, solvate or derivative thereof,wherein:

-   either R¹ is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl, benzyl, halo,    —CN, —OR⁷, —CO₂R¹⁰, —CONR⁵R¹⁰, R⁸ or R⁹, said C₁-C₆ alkyl, C₃-C₇    cycloalkyl, phenyl and benzyl being optionally substituted by halo,    —CN, —OR¹⁰, S(O)_(x)R¹⁰, —CO₂R¹⁰, —CONR⁵R¹⁰, —OCONR⁵R¹⁰,    —NR⁵CO₂R¹⁰—NR¹⁰R¹¹, —NR⁵COR¹⁰, —SO₂NR⁵R¹⁰, —NR⁵CONR⁵R¹⁰, —NR⁵SO₂R¹⁰    or R¹⁰; and-   R² is H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₇    cycloalkyl, C₃-C₇ cycloalkenyl, phenyl, benzyl, R⁸ or R⁹, said C₁-C₆    alkyl, C₃-C₇ cycloalkyl, phenyl and benzyl being optionally    substituted by halo, —OR⁵, —OR¹², —CN, —CO₂R⁷, —OCONR⁵R⁵, —CONR⁵R⁵,    —C(═NR⁵)NR⁵OR⁵, —CONR⁵NR⁵R⁵, —NR⁶R⁶, —NR⁵R¹², —NR⁵COR⁵, —NR⁵COR⁸,    —NR⁵COR¹², —NR⁵CO₂R⁵, —NR⁵CONR⁵R⁵, —SO₂NR⁵R⁵, —NR⁵SO₂R⁵,    —NR⁵SO₂NR⁵R⁵, R⁸ or R⁹;-   or, R¹ and R², when taken together, represent unbranched C₃-C₄    alkylene, optionally substituted by oxo, optionally wherein one    methylene group of said C₃-C₄ alkylene is replaced by an oxygen atom    or a nitrogen atom, said nitrogen atom being optionally substituted    by R¹⁰;-   R³ is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl, benzyl, halo, —CN,    —OR⁷, —CO₂R⁵, —CONR⁵R⁵, R⁸ or R⁹, said C₁-C₆ alkyl, C₃-C₇    cycloalkyl, phenyl and benzyl being optionally substituted by halo,    —CN, —OR⁵, —CO₂R⁵, —CONR⁵R⁵, —OCONR⁵R⁵, —NR⁵CO₂R⁵, —NR⁶R⁶, —NR⁵COR⁵,    —SO₂NR⁵R⁵, —NR⁵CONR⁵R⁵, —NR⁵SO₂R⁵, R⁸ or R⁹;-   R⁴ is phenyl, naphthyl or pyridyl, each being optionally substituted    by R⁸, halo, —CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl,    C₁-C₆ alkoxy, —CONR⁵R⁵, OR¹³, SO_(x)R⁶, O—(C₁-C₆ alkylene)-CONR⁵R⁵,    O—(C₁-C₆ alkylene)-NR⁵R⁵, or O—(C₁-C₆ alkylene)-OR⁶;-   each R⁵ is independently either H, C₁-C₆ alkyl or C₃-C₇ cycloalkyl    or, when two R⁵ groups are attached to the same nitrogen atom, those    two groups taken together with the nitrogen atom to which they are    attached represent azetidinyl, pyrrolidinyl, piperidinyl,    homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said    azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,    homopiperazinyl and morpholinyl being optionally substituted by    C₁-C₆ alkyl or C₃-C₇ cycloalkyl;-   each R⁶ is independently either H, C₁-C₆ alkyl or C₃-C₇ cycloalkyl;-   R⁷ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl;-   R⁸ is a five or six-membered, aromatic heterocyclic group    containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2    nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii)    1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group    being optionally substituted by halo, oxo, —CN, —COR⁵, —CONR⁵R⁵,    —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —OR⁵, —NR⁵R⁵, —(C₁-C₆ alkylene)-NR⁵R⁵, C₁-C₆    alkyl, fluoro(C₁-C₆)alkyl or C₃-C₇ cycloalkyl;-   R⁹ is a four to seven-membered, saturated or partially unsaturated    heterocyclic group containing (i) 1 or 2 nitrogen heteroatom(s)    or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulphur heteroatom    or (iii) 1 oxygen or sulphur heteroatom, said heterocyclic group    being optionally substituted by oxo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,    —SO₂R⁵, —CONR⁵R⁵, —COOR⁵, —CO —(C₁-C₆ alkylene)-OR⁵ or —COR⁵ and    optionally substituted on a carbon atom which is not adjacent to a    heteroatom by halo, —OR⁵, —NR⁵R⁵, —NR⁵COR⁵, —NR⁵COOR⁵, —NR⁵CONR⁵R⁵,    —NR⁵SO₂R⁵ or —CN;-   R¹⁰ is H, R⁸, R⁹, R¹³, C₁-C₆ alkyl, C₃-C₇ cycloalkyl or —(C₁-C₆    alkyl)-(C₃-C₇ cycloalkyl), said C₁-C₆ alkyl and C₃-C₇ cycloalkyl    being optionally substituted by —OR⁵, —OR¹³, R⁸, R⁹, R¹³ or —COR¹³;-   R¹¹ is H, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, said C₁-C₆ alkyl and    C₃-C₇ cycloalkyl being optionally substituted by —OR⁵, —NR⁵R⁵,    —NR⁵COR⁵, —CONR⁵R⁵, R⁸ or R⁹;-   R¹² is C₁-C₆ alkyl substituted by R⁸, R⁹, —OR⁵, —CONR⁵R⁵, —NR⁵COR⁵    or —NR⁵R⁵;-   R¹³ is phenyl optionally substituted by halo, —CN, —COR⁵, —CONR⁵R⁵,    —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —OR⁵, —NR⁵R⁵, —(C₁-C₆ alkylene)-NR⁵R⁵, C₁-C₆    alkyl, halo(C₁-C₆)alkyl or C₃-C₇ cycloalkyl; and-   x is 0, 1 or 2;    with the proviso that (a) when R¹ and R³ are both phenyl, R² is not    methyl; and (b) when R¹ is ethoxy and R³ is ethoxycarbonyl, R² is    not phenyl.

In the above definitions, halo means fluoro, chloro, bromo or iodo.Unless otherwise stated, alkyl, alkenyl, alkynyl, alkylene and alkoxygroups containing the requisite number of carbon atoms can be unbranchedor branched chain. Examples of alkyl include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkenylinclude ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-buten-1-yl,1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl,2-methylpropen-1-yl or 2-methylpropen-3-yl. Examples of alkynyl includeethynyl, propyn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl,1-butyn-4-yl, 2-butyn-1-yl. Examples of alkylene include methylene,1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propyleneand 1,3-propylene. Examples of alkoxy include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl. Where R¹ and R² are taken together, theyform, along with the nitrogen atom and the carbon atom of the pyrazolering to which they are attached, a 5- or 6-membered ring. Where aheterocyclic group R⁸ or R⁹ is attached to an oxygen, sulphur ornitrogen heteroatom the heterocyclic group R⁸ or R⁹ must be linkedthrough a ring carbon atom. Further, where a heterocyclic group R⁹ isattached to an oxygen, sulphur or nitrogen heteroatom the heterocyclicgroup R⁹ must be linked through a ring carbon atom that is not adjacentto a ring heteratom.

The pharmaceutically acceptable salts of the compounds of the formula(I) include the acid addition and the base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts and examples are the hydrochloride, hydrobromide, hydroiodide,sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate,maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate,saccharate, benzoate, methanesulphonate, ethanesulphonate,benzenesulphonate, para-toluenesulphonate and pamoate salts.

Suitable base salts are formed from bases which form non-toxic salts andexamples are the sodium, potassium, aluminium, calcium, magnesium, zincand diethanolamine salts.

For a review on suitable salts see Berge et al, J. Pharm. Sci., 66,1-19, 1977.

The pharmaceutically acceptable solvates of the compounds of the formula(I) include the hydrates thereof.

Also included within the present scope of the compounds of the formula(I) are polymorphs thereof.

The compounds of formula (I) may be modified to provide pharmaceuticallyacceptable derivatives thereof at any of the functional groups in thecompounds. Examples of such derivatives are described in: Drugs ofToday, Volume 19, Number 9, 1983, pp 499-538; Topics in Chemistry,Chapter 31, pp 306-316; and in “Design of Prodrugs” by H. Bundgaard,Elsevier, 1985, Chapter 1 (the disclosures in which documents areincorporated herein by reference) and include: esters, carbonate esters,hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides,amides, sulphonamides, carbamates, azo-compounds, phosphamides,glycosides, ethers, acetals and ketals.

A compound of the formula (I) may contain one or more asymmetric carbonatoms and therefore exist in two or more stereoisomeric forms. Thepresent invention includes the individual stereoisomers of the compoundsof the formula (I) together with, where appropriate, the individualtautomers thereof, and mixtures thereof.

Separation of diastereoisomers may be achieved by conventionaltechniques, e.g. by fractional crystallisation, chromatography or highperformance liquid chromatography (HPLC) of a stereoisomeric mixture ofa compound of the formula (I) or a suitable salt or derivative thereof.An individual enantiomer of a compound of the formula (I) may also beprepared from a corresponding optically pure intermediate or byresolution, such as by HPLC of the corresponding racemate using asuitable chiral support or by fractional crystallisation of thediastereoisomeric salts formed by reaction of the corresponding racematewith a suitable optically active acid or base, as appropriate.

Preferably, R¹, when taken separately, is H, C₁-C₆ alkyl, C₃-C₇cycloalkyl or —OR⁷, said C₁-C₆ alkyl and C₃-C₇ cycloalkyl beingoptionally substituted by halo, —CN, —OR¹⁰, S(O)_(x)R¹⁰, —CO₂R¹⁰,—CONR⁵R¹⁰, —OCONR⁵R¹⁰, —NR⁵CO₂R¹⁰, —NR¹⁰R¹¹, —NR⁵COR¹⁰, —SO₂NR⁵R¹⁰,—NR⁵CONR⁵R¹⁰, —NR⁵SO₂R¹⁰ or R¹⁰.

Preferably, R¹, when taken separately, is H, C₁-C₆ alkyl, C₃-C₇cycloalkyl or —OR⁷, said C₁-C₆ alkyl being optionally substituted byhalo, —OR¹⁰, —NR¹⁰R¹¹, —NR⁵COR¹⁰ or R¹⁰.

Preferably, R¹, when taken separately, is H, C₁-C₄ alkyl, cyclopropyl,or —OCH₃, said C₁-C₄ alkyl being optionally substituted by bromo, —OH,—O(C₁-C₂ alkyl), —NR¹⁰R¹¹, —NHCOR¹³ or R¹⁰.

Preferably, R¹, when taken separately, is H, —CH₃, —CH₂CH₃, —CH(CH₃)₂,—C(CH₃)₃, cyclopropyl, —OCH₃, —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂Br,—CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂NHCH₂(cyclopropyl),—CH₂NHCH₂CH₂OCH₃, —CH₂NHCH₂CH₂NHCOCH₃, —CH₂NHCO(4-cyanophenyl),—CH₂NHCO(3-cyanophenyl), —CH₂NHCH₂(4-cyanophenyl),—CH₂NHCH₂(4-fluorophenyl), —CH₂NHCH₂(4-methoxyphenyl),—CH₂NHCH₂(4-aminosulphonylphenyl), —CH₂NHCH₂(4-aminocarbonylphenyl),—CH₂NHCH₂(pyrid-3-yl), —CH₂N(CH₃)(4-cyanophenylmethyl),—CH₂N(CH₂CH₂OH)(4-cyanophenylmethyl), 4-methoxypiperidin-1-ylmethyl,4-aminocarbonylpiperidin-1-ylmethyl,4-methylcarbonylaminopiperidin-1-ylmethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-methylcarbonylpiperazin-1-ylmethyl,4-methoxymethylcarbonylpiperazin-1-ylmethyl,4-methoxycarbonylpiperazin-1-ylmethyl,4-methylsulphonylpiperazin-1-ylmethyl, morpholin-4-ylmethyl,2-methylimidazol-1-ylmethyl, pyrazol-1-ylmethyl or1,2,4-triazol-1-ylmethyl.

Preferably, R¹, when taken separately, is, —CH₃, —CH₂CH₃, cyclopropyl,—CH₂NHCH₂(4-cyanophenyl), —CH₂NHCH₂(4-fluorophenyl),—CH₂NHCH₂(4-methoxyphenyl), —CH₂NHCH₂(4-aminosulphonylphenyl) or—CH₂NHCH₂(4-aminocarbonylphenyl).

Preferably, R², when taken separately, is H, C₁-C₆ alkyl, C₃-C₆ alkenylor R⁹, said C₁-C₆ alkyl being optionally substituted by halo, —OR⁵,—OR², —CN, —CO₂R⁷, —OCONR⁵R⁵, —CONR⁵R⁵, —C(═NR⁵)NR⁵OR⁵, —CONR⁵NR⁵R⁵,—NR⁶R⁶, —NR⁵R¹², —NR⁵COR⁵, —NR⁵COR⁸, —NR⁵COR¹², —NR⁵CO₂R⁵, —NR⁵CONR⁵R⁵,—SO₂NR⁵R⁵, —NR⁵SO₂R⁵, R⁸ or R⁹.

Preferably, R², when taken separately, is H, C₁-C₆ alkyl, C₃-C₆ alkenylor R⁹, said C₁-C₆ alkyl being optionally substituted by —OR⁵, —OR¹²,—CN, —CO₂R⁷, —CONR⁵R⁵, —C(═NR⁵)NR⁵OR⁵, —CONR⁵NR⁵R⁵, —NR⁶R⁶, —NR⁵R¹²,—NR⁵COR⁸, —NR⁵COR¹², —NR⁵CO₂R⁵, R⁸ or R⁹.

Preferably, R², when taken separately, is H, C₁-C₃ alkyl, propenyl orR⁹, said C₁-C₃ alkyl being optionally substituted by —OH, —OCH₃,—OCH₂CH₂NH₂, —CN, —CO₂CH₃, —CO₂CH₂CH₃, —CONH₂, —C(═NH)NHOH, —CONHNH₂,—NH₂, —NHCH₃, —N(CH₃)₂, —NHCH₂CH₂NHCOCH₃, —NHCH₂CH₂OCH₃, —NHCH₂R⁹,—NHCOR⁸, —NHCOCH₂OCH₃, —NHCO₂C(CH₃)₃, R⁸ or R⁹.

Preferably, R², when taken separately, is H, methyl, —CH₂CH═CH₂, —CH₂CN,—CH₂OCH₃, —CH₂CONH₂, —CH₂CONHNH₂, —CH₂CO₂CH₃, —CH₂CO₂CH₂CH₃,—CH₂C(═NH)NHOH, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂NH₂, —CH₂CH₂NHCOCH₂OCH₃,—CH₂CH₂NHCO₂C(CH₃)₃, 2-(pyrid-2-ylcarbonylamino)eth-1-yl,2-(pyrazin-2-ylcarbonylamino)eth-1-yl, —CH₂CH₂OCH₂CH₂NH₂, —CH₂CH₂NHCH₃,—CH₂CH₂N(CH₃)₂, —CH₂CH₂NHCH₂CH₂NHCOCH₃, —CH₂CH₂NHCH₂CH₂OCH₃,—CH₂CH(OH)CH₃, (3-hydroxypyrazol-5-yl)methyl,2-hydroxy-1,3,4-oxadiazol-5-ylmethyl, 2-amino-1,3,4-oxadiazol-5-yl,5-hydroxy-1,2,4-oxadiazol-3-ylmethyl,6-hydroxy-2-methylpyrimidin-4-ylmethyl,6-hydroxy-2-aminopyrimidin-4-ylmethyl, 2-(morpholin-4-yl)eth-1-yl,2-(4-methylcarbonylpiperazin-1-yl)eth-1-yl, morpholin-3-ylmethyl,(2-(tetrahydrofuran-2-ylmethylamino)eth-1-yl, 1-methylazetidin-3-yl orazetidin-3-yl.

Preferably, R², when taken separately, is H, —CH₂CH₂OH or —CH₂CH₂NH₂.

Preferably, R¹ and R², when taken together, represent unbranched C₃-C₄alkylene, optionally substituted by oxo, wherein one methylene group ofsaid C₃-C₄ alkylene is replaced by an oxygen atom or a nitrogen atom,said nitrogen atom being optionally substituted by R¹⁰.

Preferably, R¹ and R², when taken together, represent unbranchedpropylene wherein one methylene group is replaced by an oxygen atom orunbranched butylene wherein one methylene group is replaced by anitrogen atom, said propylene and butylene being optionally substitutedby oxo and said nitrogen atom being optionally substituted by R¹⁰.

Preferably, R¹ and R², when taken together, represent ^(x)—OCH₂CH₂—^(y),^(x)—CONHCH₂CH₂—^(y), ^(x)—CH₂NHCH₂CH₂—^(y), ^(x)—CH₂N(CH₃)CH₂CH₂—^(y),^(x)—CH₂N(4-cyanophenylmethyl)CH₂CH₂—^(y) or^(x)—CH₂N(4-methoxyphenylmethyl)CH₂CH₂—^(y) wherein ‘x’ represents thepoint of attachment to the carbon atom of the pyrazole ring and ‘y’represents the point of attachment to the nitrogen atom of the pyrazolering.

Preferably, R³ is H or C₁-C₆ alkyl, said C₁-C₆ alkyl being optionallysubstituted by halo, —CN, —OR⁵, —CO₂R⁵, —CONR⁵R⁵, —OCONR⁵R⁵, —NR⁵CO₂R⁵,—NR⁶R⁶, —NR⁵COR⁵, —SO₂NR⁵R⁵, —NR⁵CONR⁵R⁵, —NR⁵SO₂R⁵, R⁸ or R⁹.

Preferably, R³ is H or C₁-C₆ alkyl.

Preferably, R³ is H or C₁-C₄ alkyl.

Preferably, R³ is H, —CH₃, —CH₂CH₃, —CH(CH₃)₂ or —C(CH₃)₃.

Preferably, R³ is —CH₃, —CH₂CH₃, —CH(CH₃)₂ or cyclopropyl.

Preferably, R⁴ is phenyl optionally substituted by R⁸, halo, —CN, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkoxy.

Preferably, R⁴ is phenyl substituted by R⁸, halo, —CN, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkoxy.

Preferably, R⁴ is phenyl substituted by halo, —CN or C₁-C₆ alkyl.

Preferably, R⁴ is phenyl substituted by fluoro, chloro, —CN or methyl.

Preferably, R⁴ is 3-cyanophenyl, 4-chlorophenyl, 3-chlorophenyl,2-chlorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3,5-dichlorophenyl,2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl,2,3-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl,3,5-dicyanophenyl, 3,5-dimethylphenyl, 4-fluoro-3-methylphenyl,3-cyano-4-fluorophenyl, 3-cyano-5-fluorophenyl, 2-chloro-4-cyanophenyl,3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl or4-cyano-2,6-dimethylphenyl.

Preferably, R⁴ is 3,5-dicyanophenyl, 3-cyano-5-fluorophenyl,3-chloro-5-cyanophenyl or 3-cyano-5-methylphenyl.

In an alternative set of preferences:

Preferably, R⁴ is phenyl optionally substituted by R⁸, halo, —CN, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, —CONR⁵R⁵, OR¹³,SO_(x)R⁶, O—(C₁-C₆ alkylene)-CONR⁵R⁵, O—(C₁-C₆ alkylene)-NR⁵R⁵, orO—(C₁-C₆ alkylene)-OR⁶; or naphthyl.

Preferably, R⁴ is phenyl substituted by R⁸, halo, —CN, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, —CONR⁵R⁵, OR¹³,SO_(x)R⁶, O—(C₁-C₆ alkylene)-CONR⁵R⁵, O—(C₁-C₆ alkylene)-NR⁵R⁵, orO—(C₁-C₆ alkylene)-OR⁶.

Preferably, R⁸ is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furanyl, thienyl,pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionallysubstituted by halo, —CN, —COR⁵, —CONR⁵R⁵, —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —OR⁵,—NR⁵R⁵, —(C₁-C₆ alkylene)-NR⁵R⁵, C₁-C₆ alkyl, fluoro(C₁-C₆)alkyl orC₃-C₇ cycloalkyl.

Preferably, R⁸ is imidazolyl, pyrazolyl, 1,2,4-triazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl orpyrimidinyl, each being optionally substituted by halo, —CN, —COR⁵,—CONR⁵R⁵, —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —OR⁵, —NR⁵R⁵, —(C₁-C₆ alkylene)-NR⁵R⁵,C₁-C₆ alkyl, fluoro(C₁-C₆)alkyl or C₃-C₇ cycloalkyl.

Preferably, R⁸ is imidazolyl, pyrazolyl, 1,2,4-triazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl orpyrimidinyl, each being optionally substituted by —OR⁵, —NR⁵R⁵ or C₁-C₆alkyl.

Preferably, R⁸ is imidazolyl, pyrazolyl, 1,2,4-triazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl orpyrimidinyl, each being optionally substituted by —OH, —NH₂ or methyl.

Preferably, R⁸ is pyrazol-1-yl, 2-methylimidazol-1-yl,1,2,4-triazol-1-yl, 3-hydroxypyrazol-5-yl,2-hydroxy-1,3,4-oxadiazol-5-yl, 2-amino-1,3,4-oxadiazol-5-yl,5-hydroxy-1,2,4-oxadiazol-3-yl, 2-methyl-4-hydroxypyrimidin-6-yl,2-amino-4-hydroxypyrimidin-6-yl, pyridin-3-yl, pyridin-2-yl orpyrazin-2-yl.

Preferably, R⁹ is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morpholinyl,piperazinyl or diazepinyl, each being optionally substituted by oxo,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, —SO₂R⁵, —CONR⁵R⁵, —COOR⁵, —CO—(C₁-C₈alkylene)-OR⁵ or —COR⁵ and optionally substituted on a carbon atom whichis not adjacent to a heteroatom by halo, —OR⁵, —NR⁵R⁵, —NR⁵COR⁵,—NR⁵COOR⁵, —NR⁵CONR⁵R⁵, —NR⁵SO₂R⁵ or —CN.

Preferably, R⁹ is azetidinyl, piperidinyl, tetrahydrofuranyl,piperazinyl or morpholinyl, each being optionally substituted by oxo,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, —SO₂R⁵, —CONR⁵R⁵, —COOR⁵, —CO—(C₁-C₆alkylene)-OR⁵ or —COR⁵ and optionally substituted on a carbon atom whichis not adjacent to a heteroatom by halo, —OR⁵, —NR⁵R⁵, —NR⁵COR⁵,—NR⁵COOR⁵, —NR⁵CONR⁵R⁵, —NR⁵SO₂R⁵ or —CN.

Preferably, R⁹ is azetidinyl, piperidinyl, tetrahydrofuranyl,piperazinyl or morpholinyl, each being optionally substituted by C₁-C₆alkyl, —SO₂R⁵, —CONR⁵R⁵, —COOR⁵, —CO—(C₁-C₆ alkylene)-OR⁵ or —COR⁵ andoptionally substituted on a carbon atom which is not adjacent to aheteroatom by —OR^(s) or —NR⁵COR⁵.

Preferably, R⁹ is azetidinyl, piperidinyl, tetrahydrofuranyl,piperazinyl or morphoninyl, each being optionally substituted by —CH₃,—SO₂CH₃, —CONH₂, —COOCH₃, —COCH₂OCH₃ or —COCH₃ and optionallysubstituted on a carbon atom which is not adjacent to a heteroatom by—OCH₃ or —NHCOCH₃.

Preferably, R⁹ is 4-methoxypiperidin-1-yl,4-aminocarbonylpiperidin-1-yl, 4-methylcarbonylaminopiperidin-1-yl,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylcarbonylpiperazin-1-yl,4-methoxymethylcarbonylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl,4-methylsulphonylpiperazin-1-yl, morpholin-4-yl, tetrahydrofuran-2-yl,morpholin-3-yl, azetidin-3-yl or 1-methylazetidin-3-yl.

Preferably, R¹⁰ is H, R⁸, R⁹, R¹³, C₁-C₆ alkyl or —(C₁-C₆ alkyl)-(C₃-C₇cycloalkyl), said C₁-C₆ alkyl being optionally substituted by —OR⁵,—OR¹³, R⁸, R⁹, R¹³ or —COR¹³.

Preferably, R¹⁰ is H, R⁸, R⁹, R¹³, C₁-C₆ alkyl or —(C₁-C₆ alkyl)-(C₃-C₇cycloalkyl), said C₁-C₆ alkyl being optionally substituted by —OR⁵ orR¹³.

Preferably, R¹⁰ is H, R⁸, R⁹, R¹³, —CH₃, —CH₂CH₃ or —CH₂(cyclopropyl),said —CH₃ and —CH₂CH₃ being optionally substituted by —OCH₃ or R¹³.

Preferably, R¹⁰ is H, R⁸, R⁹, R³, —CH₃, —CH₂CH₃, —CH₂CH₂OCH₃,—CH₂(cyclopropyl), 4-cyanophenylmethyl, 4-fluorophenylmethyl,4-methoxyphenylmethyl, 4-aminosulphonylphenylmethyl or4-aminocarbonylphenylmethyl.

Preferably, R¹¹ is H or C₁-C₆ alkyl, said C₁-C₆ alkyl being optionallysubstituted by —OR⁵, —NR⁵R⁵, —NR⁵COR⁵, —CONR⁵R⁵, R⁸ or R⁹.

Preferably, R¹¹ is H or C₁-C₆ alkyl, said C₁-C₆ alkyl being optionallysubstituted by —OR⁵ or —NR⁵COR⁵.

Preferably, R¹¹ is H, —CH₃ or —CH₂CH₃, said —CH₃ and —CH₂CH₃ beingoptionally substituted by —OH or —NHCOCH₃.

Preferably, R¹¹ is H, —CH₃, —CH₂CH₂NHCOCH₃ or —CH₂CH₂OH.

Preferably, R¹² is C₁-C₄ alkyl substituted by R⁸, R⁹, —OR⁵, —CONR⁵R⁵,—NR⁵COR⁵ or —NR⁵R⁵.

Preferably, R¹² is C₁-C₄ alkyl substituted by R⁹, —OR⁵, —NR⁵COR⁵ or—NR⁵R⁵.

Preferably, R¹² is C₁-C₂ alkyl substituted by tetrahydrofuranyl, —OCH₃,—NHCOCH₃ or —NH₂.

Preferably, R¹² is —CH₂CH₂NH₂, —CH₂CH₂OCH₃, tetrahydrofuran-2-ylmethyl,—CH₂CH₂NHCOCH₃ or —CH₂OCH₃.

Preferably, R¹³ is phenyl substituted by halo, —CN, —COR⁵, —CONR⁵R⁵,—SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —OR⁵, —NR⁵R⁵, —(C₁-C₆ alkylene)-NR⁵R⁵, C₁-C₆alkyl, halo(C₁-C₆)alkyl or C₃-C₇ cycloalkyl.

Preferably, R¹³ is phenyl substituted by halo, —CN, —CONR⁵R⁵, —SO₂NR⁵R⁵or —OR⁵.

Preferably, R¹³ is phenyl substituted by fluoro, —CN, —CONH₂, —SO₂NH₂ or—OCH₃.

Preferably, R¹³ is 4-cyanophenyl, 3-cyanophenyl, 4-fluorophenyl,4-methoxyphenyl, 4-aminocarbonylphenyl or 4-aminosulphonylphenyl.

Preferred groups of compounds according to the invention include allcombinations of the preferred definitions for individual substituentsgiven above.

Also preferred according to the invention are the compounds of formula(I)

or a pharmaceutically acceptable salt, solvate or derivative thereof,wherein:

-   R¹ is H, C₁-C₆ alkyl, —OC₁-C₆ alkyl, —OC₃-C₇ cycloalkyl, said C₁-C₆    alkyl being optionally substituted by R¹⁵;-   R² is H, C₁-C₃ alkyl, propenyl or C-linked R¹⁵, said C₁-C₃ alkyl    being optionally substituted by —OH, —OCH₃, —OCH₂CH₂NH₂, —CN,    —CO₂CH₃, —CONH₂, —C(═NH)NH₂, —CONHNH₂, —NH₂, —NHCH₃, —N(CH₃)₂,    —NHCH₂CH₂NHCOCH₃, —NHCH₂CH₂OCH₃, —NHCH₂R¹⁵, —NHCOR¹⁵, NHCOCH₂OCH₃,    or R¹⁵-   R³ is C₁-C₆ alkyl;-   R⁴ is phenyl optionally substituted by halo, —CN, C₁-C₆ alkyl, C₁-C₆    haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkoxy; and-   R¹⁵ is azetidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl,    pyrazolyl, oxadiazolyl, pyridinyl or pyrimidinyl each being    optionally substituted by —OH, —NH₂, oxo or C₁-C₆ alkyl or —CO(C₁-C₆    alkyl).

Preferred individual compounds according to the invention include theExamples below, particularly Examples 117, 118, 119, 120, 122, 123, 124,125, 126, 127 and 128, and the pharmaceutically acceptable salts andsolvates thereof.

All of the compounds of the formula (I) can be prepared by conventionalroutes such as the procedures described in the general methods presentedbelow or by the specific methods described in the Examples section, orby similar methods thereto. The present invention also encompasses anyone or more of these processes for preparing the compounds of formula(I), in addition to any novel intermediates used therein.

In the following general methods, R¹, R², R³ and R⁴ are as previouslydefined for a compound of the formula (I) unless otherwise stated.

Except where either R¹ or R³ is halo, —OR⁸ or —CN, compounds of theformula (I) may be prepared using the route shown in Scheme 1 thatfollows.

In Scheme 1, compounds of the formula (I) may be prepared by thecondensation of a compound of the formula (II) with a compound of theformulaH₂NNHR²  (V),or a salt or hydrate thereof, optionally in the presence of an acid or abase, the base preferably being a tertiary amine base such astriethylamine and the acid preferably being acetic acid. In a typicalprocedure, a solution of the compound of the formula (II) in a suitablesolvent, such as ethanol, is treated with the compound of the formula(V), or the salt or hydrate thereof, and, if used, the appropriate acidor base, at a temperature of from room temperature to the refluxtemperature of the solvent. In a preferred procedure, the reactionmixture is heated under reflux.

Functional equivalents of compounds of the formula (II) may also be usedin this reaction. These include compounds of the formula (VI) or (VII),in which L¹ and L², respectively, are each suitable leaving groups,preferably —N(C₁-C₆ alkyl)₂, most preferably —N(CH₃)₂.

Thus, a compound of the formula (I) may be prepared by the condensationof a compound of the formula (VI) or (VII) with a compound of theformula (V), or a salt or hydrate thereof, optionally in the presence ofan acid or a base, the base preferably being a tertiary amine base suchas triethylamine and the acid preferably being acetic acid. In a typicalprocedure, a solution of the compound of the formula (VI) or (VII) in asuitable solvent, such as ethanol, is treated with the compound of theformula (V), or the salt or hydrate thereof, and, if used, theappropriate acid or base, at a temperature of from room temperature tothe reflux temperature of the solvent. In a preferred procedure, thereaction mixture is heated under reflux. Compounds of the formula (VI)or (VII) are particularly suitable for the synthesis of compounds of theformula (I) in which R¹ or R³, respectively, is H.

Compounds of the formula (VI) in which R¹ is H and L¹ is dimethylaminomay be prepared by the reaction of a compound of the formula (VIII) withdimethylformamide dimethylacetal at an elevated temperature, preferablyat about 100° C. Compounds of the formula (VII) in which R¹ is H and L¹is dimethylamino may be prepared by the reaction of a compound of theformula (IX) under the same conditions. Other compounds of the formula(VI) or (VII) in which L¹ or L² is dimethylamino may be preparedanalogously.

Compounds of the formula (VIII) are either commercially available or maybe prepared by the reaction of a compound of the formulaR³COCH₂Br  (X)with a compound of the formulaR⁴OH  (XI).

In a typical procedure, a solution of the compound of the formula (XI)in a suitable solvent, such as acetone, is treated with a suitable base,such as caesium carbonate, and the compound of the formula (X). In apreferred procedure, the reaction mixture is heated, for example underreflux. Optionally, a nucleophilic catalyst such as sodium iodide ortetrabutylammonium iodide may be added

Compounds of the formula (IX) are either commercially available or maybe prepared from a compound of the formulaR¹COCH₂Br  (XII)and a compound of the formula (XI) in the same way that a compound ofthe formula (VIII) may be prepared from a compound of the formula (X).

Compounds of the formula (II) may be prepared by the reaction of acompound of the formula (III) with a compound of the formula (XI).

In a typical procedure, a solution of the compound of the formula (III)in a suitable solvent such as acetone is treated with a compound of theformula (XI) and a suitable base, such as potassium or caesiumcarbonate, and heated, preferably under reflux. Optionally, anucleophilic catalyst such as sodium iodide or tetrabutylammonium iodidemay be added.

Compounds of the formula (III) are either commercially available or maybe prepared by the reaction of a compound of the formula (IV) with achlorinating reagent. In a typical procedure, a cooled solution of thecompound of the formula (IV) in a suitable solvent such as acetonitrileis treated first with tetrabutylammonium bromide andchlorotrimethylsilane and then dry dimethylsulphoxide. In anothertypical procedure, the compound of the formula (IV) is treated withsulphuryl chloride, optionally in the presence of a suitable solventsuch as dichloromethane.

Compounds of the formula (I) in which R¹ or R³ is —OR⁸ may be preparedusing the route shown in Scheme 2 that follows, in which R^(a) is C₁-C₆alkyl and L³ is a suitable leaving group, preferablytrifluoromethanesulphonate.

In Scheme 2, compounds of the formula (I) in which R¹ is —OR⁸ may beprepared by the reaction of a compound of the formula (XIII) with analcohol of the formulaR⁸OH  (XXI)in the presence of a suitable palladium catalyst and carbon monoxide. Ina typical procedure a mixture of the compound of the formula (XIII), asuitable palladium catalyst such as1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride, the alcoholof the formula (XXI) and, optionally, a suitable solvent such asN,N-dimethylformamide is heated, preferably to about 50° C., under anatmosphere of carbon monoxide, preferably at a pressure of 345 kPa.

Compounds of the formula (XIII) may be prepared by the derivatisation ofa compound of the formula (XV). In the case where L³ istrifluoromethanesulphonate a suitable derivatising agent isphenyltriflamide. In a typical procedure, where L³ istrifluoromethanesulphonate, a solution of the compound of the formula(XV) and a suitable base, preferably a trialkylamine base such astriethylamine, in a suitable solvent such as dichloromethane is treatedwith phenyltriflamide.

Compound of the formula (XV) may be prepared by the reaction of acompound of the formula (XVII) with a compound of the formula (V), or asalt or hydrate thereof, optionally in the presence of an acid or abase, the base preferably being a tertiary amine base such astriethylamine and the acid preferably being acetic acid. In a typicalprocedure, a solution of the compound of the formula (XVII) in asuitable solvent, such as ethanol, is treated with the compound of theformula (V), or the salt or hydrate thereof, and, if used, theappropriate acid or base, at a temperature of from room temperature tothe reflux temperature of the solvent. In a preferred procedure, thereaction mixture is heated under reflux.

Compounds of the formula (XVII) may be prepared by the reaction of acompound of the formula (XIX) with a compound of the formula (XI). In atypical procedure, a solution of the compound of the formula (XVII) in asuitable solvent such as acetone is treated with a compound of theformula (XI) and a suitable base, such as potassium or caesiumcarbonate, and heated, preferably under reflux. Optionally, anucleophilic catalyst such as sodium iodide or tetrabutylammonium iodidemay be added.

In Scheme 2, compounds of the formula (I) in which R³ is —OR⁸ may beprepared from a compound of the formula (XX) in the same way that acompound of the formula (I) in which R¹ is —OR⁸ is prepared from acompound of the formula (XIX), as set out above, mutatis mutandis.

Chloroketoesters of the formula (XIX) and (XX) are either commerciallyavailable or may be prepared by the chlorination of the correspondingketoesters, for instance using sulphonyl chloride.

Alternatively, compounds of the formula (I) in which R¹ or R³ is —OR⁸may be prepared from compounds of the formula (XV) or (XVI),respectively, by reaction with a compound of the formula (XXI) underdehydrating conditions, e.g. using the Mitsunobu reaction. In a typicalprocedure, a solution of the compound of the formula (XV) or (XVI) in asuitable solvent, such as tetrahydrofuran is treated withdiethylazodicarboxylate, triphenylphosphine and a compound of theformula (XXI).

Compounds of the formula (I) in which R¹ or R³ is halo can be preparedby the reaction, respectively, of a compound of the formula (XV) or acompound of the formula (XVI) with a suitable halogenating agent. In atypical procedure, the compound of the formula (XV) or (XVI) is treatedwith POCl₃, optionally in the presence of a suitable solvent such asdimethylformamide, to give a compound of the formula (I) in which R¹ orR³, respectively, is chloro.

It will be appreciated by those skilled in the art that, in many cases,compounds of the formula (I) may be converted into other compounds ofthe formula (I) by functional group transformations. For instance:

-   (a) compounds of the formula (I) in which R² is H may be converted    into compounds of the formula (I) in which R² is optionally    substituted C₁-C₆ alkyl by reaction with an appropriate alkylating    agent. In a typical procedure, a solution of a compound of the    formula (I) in which R² is H in a suitable solvent such as ethanol    or N,N-dimethylformamide is treated with an alkyl bromide and a base    such as sodium ethoxide or sodium hydride and heated at a    temperature of from room temperature to the reflux temperature of    the solvent. A preferred combination is N,N-dimethylformamide as the    solvent, sodium hydride as the base and room temperature as the    temperature. Examples of specific alkylating agents include    bromoacetonitrile, ethyl 4-chloroacetoacetate, methyl bromoacetate    and chloroethylamine hydrochloride. The use of further specific    alkylating agents is illustrated by the Examples below;-   (b) compounds of the formula (I) in which R¹, R² or R³ contains an    ester functionality may be reduced with a suitable reducing agent,    such as lithium aluminium hydride, to give corresponding compounds    of the formula (I) in which R¹, R² or R³ contains a hydroxy group.    In a typical procedure, a solution of the compound of the formula    (I), in which R¹, R² or R³ contains an ester group, in a suitable    solvent, such as diethyl ether, is treated with lithium aluminium    hydride, preferably with cooling to a temperature of from −78° C. to    0° C.;-   (c) compounds of the formula (I) in which R¹, R² or R³ are    substituted by a heterocycle of the formula R⁶ may be prepared by    standard heterocycle-forming reactions well known to the skilled man    (see, for example, Advanced Organic Chemistry, 3rd Edition, by Gerry    March or Comprehensive Heterocyclic Chemistry, A. R.    Katritzky, C. W. Rees, E. F. V. Scriven, Volumes 1-11). For    instance, compounds of the formula (I) in which R² is    (2-amino-6-hydroxypyrimidin-4-yl)methyl may be prepared by the    sequential reaction of a compound of the formula (I) in which R² is    H with chloroacetoacetate and then guanidine hydrochloride. This and    other similar heterocyle-forming reactions are illustrated by the    Examples below; and-   (d) compounds of the formula (I) in which R¹ or R³ is —CO₂R⁵,    wherein R⁵ is other than H, may be converted into compounds of the    formula (I) in which R¹ or R³, respectively, is —CO₂H by hydrolysis.    Typically the reaction will be carried out in a suitable solvent,    such as aqueous ethanol, or aqueous 1,4-dioxan and in the presence    of a base such as sodium hydroxide. Such an acid may be converted to    a primary amide by reaction with ammonia and a suitable coupling    agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide. Such a    primary amide may then be converted into a nitrile by dehydration    with a suitable dehydrating agent, such as phosphoryl chloride.-   (e) compounds of the formula (I) in which R¹ or R³ is C₁-C₆ alkyl    may be converted into the compounds of the formula (I) in which R¹    or R³, respectively, is C₁-C₆ alkyl substituted by halo (such as    bromo), by halogenation, using a suitable halogenating agent.    Conveniently the reaction is effected in the presence of a solvent,    such as a haloalkane (e.g. dichloromethane) and at ambient    temperature. Suitable halogenating agents include halogens (e.g.    bromine) or N-halosuccinimides (e.g. N-bromsuccinimide).

Compounds of the formula (I) containing an —OH, —NH— or —NH₂ group maybe prepared by the deprotection of the corresponding compound bearing an—OP¹, —NP¹— or —NHP¹ group, respectively, wherein the group P¹ is asuitable protecting group. Examples of suitable protecting groups willbe apparent to the skilled person [see, for instance, ‘Protecting groupsin Organic Synthesis (Second Edition)’ by Theodora W. Green and Peter G.M. Wuts, 1991, John Wiley and Sons]. Such compounds bearing an —OP¹,—NP¹— or —NHP¹ group may be prepared using the routes described above,mutatis mutandis.

Compounds of the formula (IV), (V) and (XXI) are either commerciallyavailable or easily prepared by methods well known to those skilled inthe art.

The compounds of the formula (I) can be administered alone but willgenerally be administered in admixture with a suitable pharmaceuticalexcipient, diluent or carrier selected with regard to the intended routeof administration and standard pharmaceutical practice.

For example, the compounds of the formula (I) can be administeredorally, buccally or sublingually in the form of tablets, capsules,multi-particulates, gels, films, ovules, elixirs, solutions orsuspensions, which may contain flavouring or colouring agents, forimmediate-, delayed-, modified-, sustained-, pulsed- orcontrolled-release applications. The compounds of the formula (I) mayalso be administered as fast-dispersing or fast-dissolving dosage formsor in the form of a high energy dispersion or as coated particles.Suitable formulations of the compounds of the formula (I) may be incoated or uncoated form, as desired.

Such solid pharmaceutical compositions, for example, tablets, maycontain excipients such as microcrystalline cellulose, lactose, sodiumcitrate, calcium carbonate, dibasic calcium phosphate, glycine andstarch (preferably corn, potato or tapioca starch), disintegrants suchas sodium starch glycollate, croscarmellose sodium and certain complexsilicates, and granulation binders such as polyvinylpyrrolidone,hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, stearic acid, glyceryl behenate and talc may beincluded.

General Example

A formulation of the tablet could typically contain from 0.01 mg to 500mg of active compound whilst tablet fill weights may range from 50 mg to1000 mg. An example of a formulation for a 10 mg tablet is illustratedbelow:

Ingredient % w/w Compound of the formula (I) or salt 10.000* Lactose64.125 Starch 21.375 Croscarmellose sodium 3.000 Magnesium Stearate1.500 *Quantity adjusted in accordance with drug activity.

The tablets are manufactured by a standard process, for example, directcompression or a wet or dry granulation process. The tablet cores may becoated with appropriate overcoats.

Solid compositions of a similar type may also be employed as fillers ingelatin or HPMC capsules. Preferred excipients in this regard includelactose, starch, a cellulose, milk sugar or high molecular weightpolyethylene glycols. For aqueous suspensions and/or elixirs, thecompounds of the formula (I) may be combined with various sweetening orflavouring agents, colouring matter or dyes, with emulsifying and/orsuspending agents and with diluents such as water, ethanol, propyleneglycol and glycerin, and combinations thereof.

The compounds of the formula (I) can also be administered parenterally,for example, intravenously, intra-arterially, intraperitoneally,intrathecally, intraventricularly, intraurethrally, intrasternally,intracranially, intramuscularly or subcutaneously, or they may beadministered by infusion or needleless injection techniques. For suchparenteral administration they are best used in the form of a sterileaqueous solution which may contain other substances, for example, enoughsalts or glucose to make the solution isotonic with blood. The aqueoussolutions should be suitably buffered (preferably to a pH of from 3 to9), if necessary. The preparation of suitable parenteral formulationsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well-known to those skilled in the art.

For oral and parenteral administration to human patients, the dailydosage level of the compounds of the formula (I) will usually be from0.01 to 30 mg/kg, preferably from 0.01 to 5 mg/kg (in single or divideddoses).

Thus tablets or capsules of the compound of the formula (I) may containfrom 1 to 500 mg of active compound for administration singly or two ormore at a time, as appropriate. The physician in any event willdetermine the actual dosage which will be most suitable for anyindividual patient and it will vary with the age, weight and response ofthe particular patient. The above dosages are exemplary of the averagecase. There can, of course, be individual instances where higher orlower dosage ranges are merited and such are within the scope of thisinvention. The skilled person will appreciate that, in the treatment ofcertain conditions the compounds of the formula (I) may be taken as asingle dose as needed or desired.

The compounds of formula (I) can also be administered intranasally or byinhalation and are conveniently delivered in the form of a dry powderinhaler or an aerosol spray presentation from a pressurised container,pump, spray, atomiser or nebuliser, with or without the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbondioxide or other suitable gas. In the case of a pressurised aerosol, thedosage unit may be determined by providing a valve to deliver a meteredamount. The pressurised container, pump, spray, atomiser or nebulisermay contain a solution or suspension of the active compound, e.g. usinga mixture of ethanol and the propellant as the solvent, which mayadditionally contain a lubricant, e.g. sorbitan trioleate. Capsules andcartridges (made, for example, from gelatin) for use in an inhaler orinsufflator may be formulated to contain a powder mix of a compound ofthe formula (I) and a suitable powder base such as lactose or starch.

Alternatively, the compounds of the formula (I) can be administered inthe form of a suppository or pessary, or they may be applied topicallyin the form of a gel, hydrogel, lotion, solution, cream, ointment ordusting powder. The compounds of the formula (I) may also be dermally ortransdermally administered, for example, by the use of a skin patch.They may also be administered by the pulmonary or rectal routes.

They may also be administered by the ocular route. For ophthalmic use,the compounds can be formulated as micronised suspensions in isotonic,pH adjusted, sterile saline, or, preferably, as solutions in isotonic,pH adjusted, sterile saline, optionally in combination with apreservative such as a benzylalkonium chloride. Alternatively, they maybe formulated in an ointment such as petrolatum.

For application topically to the skin, the compounds of the formula (I)can be formulated as a suitable ointment containing the active compoundsuspended or dissolved in, for example, a mixture with one or more ofthe following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water. Alternatively, they can be formulated as a suitablelotion or cream, suspended or dissolved in, for example, a mixture ofone or more of the following: mineral oil, sorbitan monostearate, apolyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the formula (I) may also be used in combination with acyclodextrin. Cyclodextrins are known to form inclusion andnon-inclusion complexes with drug molecules. Formation of adrug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described inWO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

It is to be appreciated that all references herein to treatment includecurative, palliative and prophylactic treatment.

Oral administration is preferred.

Included within the scope of the present invention are embodimentscomprising the co-administration of a compound of the present inventionwith one or more additional therapeutic agents, and compositionscontaining a compound of the present invention along with one or moreadditional therapeutic agents. Such a combination therapy is especiallyuseful for the prevention and/or treatment of infection by HIV andrelated retroviruses which may evolve rapidly into strains resistant toany monotherapy. Alternatively, additional therapeutic agents may bedesirable to treat diseases and conditions which result from oraccompany the disease being treated with the compound of the presentinvention. For example, in the treatment of an HIV or related retroviralinfection, it may be desirable to additionally treat opportunisticinfections, neoplasms and other conditions which occur as a result ofthe immuno-compromised state of the patient being treated.

Preferred combinations of the present invention include simultaneous orsequential treatment with a compound of the formula (I), as definedabove, or a pharmaceutically acceptable salt thereof, and:

-   (a) one or more reverse transcriptase inhibitors such as zidovudine,    didanosine, zalcitabine, stavudine, lamivudine, abacavir and    adefovir;-   (b) one or more non-nucleoside reverse transcriptase inhibitors such    as nevirapine, delavirdine and efavirenz;-   (c) one or more HIV protease inhibitors such as indanivir,    ritonavir, saquinavir and nelfinavir;-   (d) one or more CCR5 antagonists such as TAK-779;-   (e) one or more CXCR4 antagonists such as AMD-3100;-   (f) one or more integrase inhibitors;-   (g) one or more inhibitors of viral fusion such as T-20;-   (h) one or more investigational drugs such as trizivir, KNI-272,    amprenavir, GW-33908, FTC, PMPA, S-1153, MKC-442, MSC-204, MSH-372,    DMP450, PNU-140690, ABT-378, KNI-764, DPC-083, TMC-120 or TMC-125;    or-   (i) one or more antifungal or antibacterial agents such as    fluconazole.

The activity of the compounds of the invention as reverse transcriptaseinhibitors and as agents for treating HIV infections may be measuredusing the following assays.

A. Inhibition of HIV-1 Reverse Transcriptase Enzyme

The reverse transcriptase activity of the compounds of the invention maybe assayed as following. Using the purified recombinant HIV-1 reversetranscriptase (RT, EC, 2.7.7.49) obtained by expression in EscherichiaColi, a 96-well plate assay system was established for assaying a largenumber of samples using either the Poly(rA)-oligo(dT) ReverseTranscriptase [3H]-SPA enzyme assay system (Amersham NK9020) or the[3H]-flashplate enzyme assay system (NEN-SMP 103) and following themanufacturer's recommendations. The compounds were dissolved in 100%DMSO and diluted with the appropriate buffer to a 5% final DMSOconcentration. The inhibitory activity was expressed in percentinhibition relative to the DMSO control. The concentration at which thecompound inhibited the reverse transcriptase by 50% was expressed as theIC₅₀ of the compound. The compounds of examples 7, 20 and 51, whentested according to the above procedure, had IC₅₀ values of,respectively, 39000, 3200 and 248 nanomolar.

B. Anti-Human Immunodeficiency Virus (HIV-1) Cell Culture Assay

The anti-HIV activity of selected Examples of the invention was assayedby the following procedures.

-   1) SupT1 cells were cultured in an RPMI-1640 medium supplemented    with 10% foetal calf serum and were split so that they were in    growth phase on the day of use.-   2) The compounds were dissolved in 100% DMSO and diluted with the    above culture medium to predetermined concentrations and distributed    in 20 μl aliquots into a 96-well microtiter plate (0.1% DMSO final    concentration).-   3) To prepare infected cells, 100 μl of RF viruses (TCID50 of    10⁷/ml) were added to 10⁶ cells and incubated for 1 hour at 37° C.    The cells were then washed twice in PBS and resuspended in the    culture medium at a density of 2.2×10⁵ cells/ml. 180 μl of these    infected cells was transferred to wells of the 96 well plate    containing the compounds.-   4) The plate was incubated in a CO₂ incubator at 37° C. for 4 days.    The cell survival rates were measured following the manufacturer's    recommendations (CellTiter 96® AQ_(ueous) Non-Radioactive    Assay—Promega (cat no: G5430)). The concentration at which the    compound inhibited the cytotoxic effect of the virus by 50% was    expressed as the EC₅₀.    Thus the invention provides:    -   (i) a compound of the formula (I) or a pharmaceutically        acceptable salt, solvate or derivative thereof;    -   (ii) a process for the preparation of a compound of the        formula (I) or a pharmaceutically acceptable salt, solvate or        derivative thereof;    -   (iii) a pharmaceutical composition including a compound of the        formula (I) or a pharmaceutically acceptable salt, solvate or        derivative thereof, together with a pharmaceutically acceptable        excipient, diluent or carrier;    -   (iv) a compound of the formula (I) or a pharmaceutically        acceptable salt, solvate or composition thereof, for use as a        medicament;    -   (v) a compound of the formula (I) or a pharmaceutically        acceptable salt, solvate or composition thereof, for use as a        reverse transcriptase inhibitor or modulator;    -   (vi) a compound of the formula (I) or a pharmaceutically        acceptable salt, solvate or composition thereof, for use in the        treatment of an HIV, or genetically-related retroviral,        infection or a resulting acquired immune deficiency syndrome        (AIDS);    -   (vii) the use of a compound of the formula (I) or of a        pharmaceutically acceptable salt, solvate or composition        thereof, for the manufacture of a medicament having reverse        transcriptase inhibitory or modulating activity;    -   (viii) the use of a compound of the formula (I) or of a        pharmaceutically acceptable salt, solvate or composition        thereof, for the manufacture of a medicament for the treatment        of an HIV, or genetically-related retroviral, infection or a        resulting acquired immune deficiency syndrome (AIDS);    -   (ix) a method of treatment of a mammal, including a human being,        with a reverse transcriptase inhibitor or modulator including        treating said mammal with an effective amount of a compound of        the formula (I) or with a pharmaceutically acceptable salt,        solvate or composition thereof;    -   (x) a method of treatment of a mammal, including a human being,        to treat an HIV, or genetically-related retroviral, infection or        a resulting acquired immune deficiency syndrome (AIDS) including        treating said mammal with an effective amount of a compound of        the formula (I) or with a pharmaceutically acceptable salt,        solvate or composition thereof; and    -   (xi) certain novel intermediates disclosed herein.

The following Examples illustrate the preparation of the compounds ofthe formula (I). The synthesis of certain intermediates used therein aredescribed in the Preparations section that follows the Examples.

¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistentwith the proposed structures. Characteristic chemical shifts (δ) aregiven in parts-per-million downfield from tetramethylsilane usingconventional abbreviations for designation of major peaks: e.g. s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.The following abbreviations have been used: HRMS, high resolution massspectrometry; hplc, high performance liquid chromatography; nOe, nuclearOverhauser effect; m.p., melting point; CDCl₃, deuterochloroform;D₆-DMSO, deuterodimethylsulphoxide; CD₃OD, deuteromethanol. Where thinlayer chromatography (TLC) has been used it refers to silica gel TLCusing silica gel 60 F₂₅₄ plates, R_(f) is the distance traveled by acompound divided by the distance traveled by the solvent front on a TLCplate.

EXAMPLE 12-[4-(3,5-Dichlorophenoxy)-3,5-dimethyl-1H-pyrazol-1-yl]ethanol

2-Hydroxyethyl hydrazine (21.5 μL, 0.316 mmol) was added to a stirredsolution of the β-diketone of Preparation 1 (75 mg, 0.287 mmol) inethanol (2.9 ml) at room temperature under nitrogen and the resultingorange solution was heated under reflux for 18 hours. After cooling, themixture was concentrated under reduced pressure. The residue wasdissolved in dichloromethane (20 ml) and washed with 2M hydrochloricacid (10 ml) and brine (10 ml) and then dried over magnesium sulphate,filtered and concentrated under reduced pressure to leave a viscousorange oil. The crude product was purified by flash chromatography onsilica gel eluting with pentane:ethyl acetate (10:1, by volume) thendichloromethane to provide the title compound (32 mg) as a white powder,m.p. 114-115° C.

¹H-NMR (400 MHz, CDCl₃): δ=2.08 (s, 3H), 2.10 (s, 3H), 3.30 (t, 1H),4.06 (m, 4H), 6.79 (s, 2H), 7.01 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 301.

Microanalysis: Found: C, 51.76; H, 4.64; N, 9.20. C₁₃H₁₄Cl₂N₂O₂ requiresC, 51.85; H, 4.69; N, 9.30%.

EXAMPLE 2 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethanol

3,5-Dichlorophenol (501 mg, 3.07 mmol), potassium carbonate (467 mg,3.38 mmol) and finally sodium iodide (461 mg, 3.07 mmol) were addedsequentially to a stirred solution of the chloroketone of Preparation 2(500 mg, 3.07 mmol) in acetone (15 ml), at room temperature and undernitrogen, producing an orange/red suspension. The mixture was heatedunder reflux for 22½ hours producing a yellow suspension. After coolingthe mixture was diluted with water (10 ml) and the acetone was removedunder reduced pressure in a fumehood (caution: possible residuallachrymator). The residue was diluted with 2M hydrochloric acid andextracted with dichloromethane (1×20 ml, 2×10 ml). The combined organiclayers were washed with brine (20 ml), dried over magnesium sulphate,filtered and concentrated under reduced pressure to leave crude4-(3,5-dichlorophenoxy)-3,5-heptanedione as an orange oil (777 mg). Aportion of the crude 4-(3,5-dichlorophenoxy)-3,5-heptanedione (250 mg,ca. 0.865 mmol) was dissolved in ethanol (8.6 ml) and treated with2-hydroxethyl hydrazine (65 μL, 0.951 mmol). The resulting solution washeated under reflux for 16 hours producing a red solution. Aftercooling, the mixture was concentrated under reduced pressure and theresidue was dissolved in dichloromethane (20 ml). The resulting solutionwas washed with 2M hydrochloric acid (10 ml), 1N sodium hydroxidesolution (10 ml) and brine (10 ml), dried over magnesium sulphate,filtered and concentrated under reduced pressure to leave an orange oil(102 mg). The crude product was purified by flash chromatography onsilica gel eluting with methanol:dichloromethane (5:95, by volume) toprovide the title compound (23 mg) as an orange oil which solidified toa waxy solid on standing.

¹H-NMR (400 MHz, CDCl₃): δ=1.08 (t, 3H), 1.12 (t, 3H), 2.38 (q, 2H),2.48 (q, 2H), 3.69 (br.s, 1H), 4.02 (m, 4H), 6.76 (s, 2H), 6.97 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 329.

EXAMPLE 3 4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-Pyrazole

A mixture of the chloroketone of Preparation 2 (5 g, 30.8 mmol),3,5-dichlorophenol (5 g, 30.8 mmol), caesium carbonate (10 g, 30.8 mmol)and acetone (40 ml) was heated under reflux for 18 hours. After cooling,a solid was removed by filtration and washed with dichloromethane (100ml). The combined filtrates were concentrated under reduced pressure.The crude product was dissolved in ethanol (20 ml), hydrazine hydrate(1.5 ml, 30.8 mmol) was added and the mixture was heated at 60° C. for30 minutes under nitrogen. After cooling, the mixture was concentratedunder reduced pressure and the residue was purified by flashchromatography on silica gel eluting with ether:pentane (1:1, by volume)to provide the title compound (5.5 g) as a yellow oil which solidifiedon standing to leave a yellow solid, m.p. 114-115° C.

¹H-NMR (300 MHz, CDCl₃): δ=1.15 (6H, t), 2.48 (4H, q), 6.78 (2H, s),6.95 (1H, s).

LRMS (thermospray): m/z [MH⁺] 285.

Microanalysis: Found: C, 54.93; H, 5.05; N, 9.94. C₁₃H₁₄Cl₂N₂O requiresC, 54.75; H, 4.95; N, 9.82%.

EXAMPLE 4[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetonitrile

Sodium hydride (60% dispersion in oil, 470 mg, 11.8 mmol) was added to astirred solution of 4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole (3g, 10.5 mmol, Example 3) in dry N,N-dimethylformamide (20 ml) at 0° C.under nitrogen. The mixture was stirred for 5 minutes during which timehydrogen was evolved and then bromoacetonitrile (0.81 ml, 11.6 mmol) wasadded. The yellow solution turned dark brown and a precipitate formed.Further dry N,N-dimethylformamide (5 ml) was added to aid dissolutionand after 45 minutes the reaction mixture was quenched by the additionof water (1 ml). The mixture was partitioned between water (150 ml) anddiethyl ether (2×150 ml). The combined organic layers were washed withwater (50 ml) and brine (100 ml), dried over magnesium sulphate andconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel eluting with dichloromethane toprovide the title compound (3.2 g) as a yellow powder, m.p. 70-72° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.14 (6H, m), 2.38 (2H, q), 2.56 (2H, q),4.92 (2H, s), 6.75 (2H, s), 7.00 (1H, s).

Microanalysis: Found: C, 55.43; H, 4.69; N, 12.71. C₁₅H₁₅Cl₂N₃O requiresC, 55.57; H, 4.60; N, 12.96%.

EXAMPLE 55-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]methyl}-1H-pyrazol-3-ol

A mixture of the ester (120 mg, 0.29 mmol) of Preparation 3, hydrazinehydrate (16 mg, 0.29 mmol) and ethanol (5 ml) was stirred and heated at60° C. for 2 hours under nitrogen. After cooling, the mixture wasconcentrated under reduced pressure and the resulting white solid wasstirred in ethyl acetate and then collected by filtration to give thetitle compound (60 mg) as a white solid, m.p. 142-144° C.

¹H-NMR (400 MHz, DMSO-d₆): δ=0.89 (3H, t), 0.99 (3H, t), 2.26 (2H, q),2.45 (2H, q), 5.01 (2H, s), 5.19 (1H, s), 6.88 (2H, s), 7.21 (1H, s).

LRMS (electrospray): m/z [M-H⁺] 379.

Microanalysis: Found: C, 55.39; H, 4.72; N, 14.69. C₁₇H₁₈Cl₂N₄O₂requires C, 53.56; H, 4.76; N, 14.69%.

EXAMPLE 66-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]methyl}-2-methyl-4(3H)-pyrimidinone

A mixture of the ester (140 mg, 0.34 mmol) of Preparation 3, acetamidinehydrochloride (95 mg, 1.0 mmol), sodium ethoxide (68 mg, 1.0 mmol) andethanol (5 ml) was stirred and heated at 70° C. for 1 hour undernitrogen. After cooling, the mixture was concentrated under reducedpressure. The resulting oil was dissolved in dichloromethane (50 ml),washed with water (20 ml), dried over magnesium sulphate andconcentrated under reduced pressure to leave the title compound as awhite foam (100 mg).

¹H-NMR (300 MHz, CDCl₃): δ=1.10 (3H, t), 1.19 (3H, t), 2.48 (7H, m),5.08 (2H, s), 5.72 (1H, s), 6.82 (2H, s), 7.03 (1H, s).

LRMS (thermospray): m/z [MH⁺] 407.

EXAMPLE 72-Amino-6-{[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]methyl}-4(3H)-pyrimidinone

A mixture of the ester (150 mg, 0.365 mmol) from Preparation 3 andguanidine hydrochloride (104 mg, 1.08 mmol) and sodium ethoxide (73 mg,1.08 mmol) in ethanol (5 ml) was stirred and heated at 70° C. for 3hours under nitrogen. After cooling the mixture was concentrated underreduced pressure and the resulting oil was dissolved in dichloromethane(50 ml), washed with water (20 ml), dried over magnesium sulphate andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel eluting withdichloromethane:methanol:ammonia (90:10:1, by volume) to give the titlecompound as a white solid (30 mg), m.p. 238-240° C.

¹H-NMR (400 MHz, DMSO-d₆): δ=0.91 (3H, t), 0.99 (3H, t), 2.29 (2H, q),2.44 (2H, q), 4.75 (1H, s), 4.81 (2H, s), 6.58 (2H, br.s), 6.87 (2H, s),7.22 (1H, s).

LRMS (thermospray): m/z [MH⁺] 408.

EXAMPLE 82-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N-hydroxyethanimidamide

Hydroxylamine hydrochloride (1.1 g, 15.8 mmol) and potassium carbonate(2.1 g, 15.2 mmol) were added to a suspension of the nitrile (1 g, 3.1mmol) of Example 4 in a mixture of methanol (25 ml) and water (10 ml)which was then heated under reflux for 3 days. After cooling, themixture was extracted with dichloromethane (2×250 ml) and the combinedorganic layers were washed with brine (100 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure to afford theproduct as a white solid (1.1 g), m.p. 128-130° C.

¹H-NMR (300 MHz, CD₃OD): δ=1.10 (6H, m), 2.40 (2H, q), 2.60 (2H, q),4.65 (2H, s), 6.90 (2H, s), 7.10 (1H, s).

LRMS (electrospray): m/z [MH⁺] 357.

EXAMPLE 9Methyl[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetate

Methyl bromoacetate (984 μL, 10 mmol) and then sodium hydride (60%dispersion in oil, 801 mg, 20.1 mmol) were added to a stirred solutionof the pyrazole (2.6 g, 9.12 mmol) of Example 3 in dryN,N′-dimethylformamide (25 ml) at 0° C. under nitrogen. After stirringfor 1 hour at 0° C. ice-water (100 ml) was added and the mixture wasextracted with ether (3×50 ml). The combined ether layers were driedover magnesium sulphate, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with ethyl acetate:pentane (20:80, by volume) to provide thetitle compound (780 mg) as a yellow oil which partly crystallised onstanding.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (6H, m), 2.44 (4H, m), 3.78 (3H, s),4.80 (2H, s), 6.69 (2H, s), 6.99 (1H, s).

LRMS (thermospray): m/z [MH⁺] 357.

EXAMPLE 102-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetamide

1,1′-Carbonyl diimidazole (71 mg, 0.44 mmol) was added to stirredsolution of the acid (125 mg, 0.36 mmol) of Preparation 4 in dryN,N-dimethylformamide at room temperature and the reaction mixture wasstirred for 30 minutes. Concentrated aqueous ammonia (d=0.8809/cm³, ca.0.1 ml, ca. 1.8 mmol) was added and stirring was continued for 10minutes. The solvent was removed under reduced pressure and the residuewas partitioned between water (10 ml) and ethyl acetate (10 ml). Theorganic layer was concentrated under reduced pressure and the residuewas purified by chromatography on silica gel, eluting with ethylacetate, to give the title compound as a white solid (60 mg), m.p.164-166° C.

¹H-NMR (300 MHz, CDCL₃): δ=1.15 (6H, m), 2.50 (4H, m), 4.70 (2H, s),5.50 (1H, br. s), 6.21 (1H, br. s), 6.78 (2H, s), 7.04 (1H, s).

LRMS (thermospray): m/z [MH⁺] 342.

EXAMPLE 112-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetohydrazide

Hydrazine hydrate (520 μL, 10.9 mmol) was added to a solution of theester (780 mg, 2.18 mmol) of Example 9 in ethanol (25 ml) and theresulting mixture was heated under reflux for 18 hours. After cooling,the precipitate was collected by filtration and washed with ether (50ml) to afford the title compound (550 g) as a white solid, m.p.>250° C.

¹H-NMR (300 MHz, CD₃OD): δ=1.10 (6H, m), 2.39 (2H, q), 2.55 (2H, q),4.72 (2H, s), 6.93 (2H, s), 7.09 (1H, s).

LRMS (electrospray): m/z [MH⁺] 357.

EXAMPLE 125-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]methyl}-1,3,4-oxadiazol-2(3H)-one

A stirred solution of the hydrazide (275 mg, 0.77 mmol) of Example 11and 1,1′-carbonyl diimidazole 187 mg, 1.16 mmol) in dioxane (50 ml) washeated under reflux for 18 hours. After cooling, the mixture wasconcentrated under reduced pressure and the residue was dissolved indichloromethane (50 ml) and washed with water (25 ml). The organic layerwas dried over magnesium sulphate, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane:methanol (95:5, by volume) toafford the title compound (112 mg) as a white solid m.p. 138-142° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (6H, m), 2.40 (2H, q), 2.55 (2H, q),5.07 (2H, s), 6.76 (2H, s), 6.98 (1H, s), 10.45 (1H, br. s).

LRMS (electrospray): m/z [MH⁺] 383.

EXAMPLE 132-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethylamine

A mixture of the pyrazole (390 mg, 1.37 mmol) of Example 3 andchloroethylamine hydrochloride (238 mg, 2.05 mmol) was stirred andheated at 150° C. for 24 hours. After cooling, the mixture waspartitioned between saturated aqueous sodium bicarbonate solution (100ml) and dichloromethane (2×50 ml). The combined organic layers werewashed with brine (30 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The resulting brown oil waspurified by flash chromatography on silica gel eluting withdichloromethane:methanol (90:10, by volume) to afford the title compound(244 mg) as a brown oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.09 (6H, m), 2.41 (2H, q), 2.52 (2H, q),3.18 (2H, t), 4.02 (2H, t), 6.78 (2H, s), 6.99 (1H, s).

LRMS (electrospray): m/z [MH⁺] 330.

Microanalysis: Found: C, 52.28; H, 5.70; N, 11.75. C₁₅H₁₉Cl₂N₃O.H₂Orequires C, 52.03; H, 6.11; N, 12.14%.

EXAMPLE 143-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]methyl}-1,2,4-oxadiazol-5-ol

Ethylchloroformate (0.30 ml, 3.08 mmol) was added to a stirred solutionof the amidoxime of Example 8 (500 mg, 1.39 mmol) in pyridine (8 ml) at0° C. under nitrogen and the resulting solution was stirred for 10minutes. The mixture was concentrated under reduced pressure and theresidue was dissolved in a mixture of water (4 ml), tetrahydrofuran (4ml) and 1M aqueous sodium hydroxide solution (2 ml). The mixture washeated under reflux for 1 hour, cooled to room temperature and stirredfor a further 2 days. The resulting solution was diluted with 2M aqueoushydrochloric acid (20 ml) and extracted with ethyl acetate (2×50 ml).The combined organic layers were washed with brine (50 ml), dried overmagnesium sulphate, filtered and evaporated under reduced pressure toleave a yellow oil. The oil was purified by flash column chromatographyon silica gel eluting with pentane:ethyl acetate (50:50, by volume) toyield a white solid. The solid was dissolved in a mixture oftetrahydrofuran (1 ml) and 1M aqueous sodium hydroxide solution (10 ml)and then heated under reflux for 24 hours. The resulting solution wasdiluted with 2M hydrochloric acid (20 ml) and extracted withdichloromethane (2×50 ml). The combined organic layers were washed withbrine (50 ml), dried over magnesium sulphate, filtered and evaporatedunder reduced pressure to give the title compound (113 mg) as a whitesolid m.p. 94-96° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.14 (m, 6H), 2.56 (m, 4H), 5.06 (s, 2H),6.75 (s, 2H), 7.03 (s, 1H).

LRMS (electrospray): m/z [M-(H⁺)] 381.

EXAMPLE 155-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]methyl}-1,3,4-oxadiazol-2-amine

Cyanogen bromide (49 mg, 0.462 mmol) was added to a stirred solution ofthe hydrazide of Example 11 (150 mg, 0.420 mmol) in ethanol (30 ml), atroom temperature, under nitrogen and the resulting solution was heatedto reflux for 2.5 hours. After cooling, the mixture was concentratedunder reduced pressure to leave a brown oil. The crude product waspurified by flash column chromatography on silica gel eluting withdichloromethane:methanol:ammonia (98:1.75:0.25, by volume) to providethe title compound (71 mg) as a white powder, m.p. 226-228° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.00 (m, 6H), 2.29 (m, 2H), 2.55 (m, 2H),5.34 (s, 2H), 6.90 (s, 2H), 7.07 (s, 2H), 7.24 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 382.

Microanalysis: Found: C, 49.82; H, 4.52; N, 17.81. C₁₆H₁₇Cl₂N₅O₂.0.25H₂Orequires C, 49.69; H, 4.56; N, 18.11%.

EXAMPLE 16N-{2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl}-2-methoxyacetamide

A solution of the pyrazole of Example 13 (53 mg, 0.161 mmol),1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (34 mg,0.178 mmol) and 4-(dimethylamino)pyridine (22 mg, 0.178 mmol) indichloromethane (1 ml) was added to a stirred solution of methoxyaceticacid (14.2 μL, 0.178 mmol) in dichloromethane (1 ml) at roomtemperature. The reaction was stirred for 12 hours and then concentratedunder a stream of nitrogen to leave a yellow solid. The crude productwas purified by flash column chromatography on silica gel eluting withdichloromethane:methanol (98:2, by volume) to provide the title compound(54 mg) as a brown solid, m.p. 75-76° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.08 (t, 3H), 1.18 (t, 3H), 2.42 (q, 2H),2.52 (q, 2H), 3.39 (s, 3H), 3.75 (m, 2H), 3.90 (s, 2H), 4.13 (t, 2H),6.79 (s, 2H), 6.99 (s, 1H), 7.21 (br s, 1H).

LRMS (electrospray): m/z [MH⁺] 400; [M-(H⁺)] 398.

Microanalysis: Found: C, 54.09; H, 5.79; N, 10.39. C₁₈H₂₃Cl₂N₃O₃requires C, 54.01; H, 5.79; N, 10.50%.

EXAMPLES 17 AND 18

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 16 using theappropriate acid starting material and the pyrazole of Example 13.

LRMS Example No. R (thermospray) Analytical Data 17

m/z [MH⁺] 433 ¹H-NMR (400 MHz, CDCl₃): δ = 1.06 (t, 3H), 1.18 (t, 3H),2.44 (q, 2H), 2.52 (q, 2H), 3.92 (m, 2H), 4.24 (t, 2H), 6.79 (s, 2H),6.99 (s, 1H), 7.40 (m, 1H), 7.82 (m, 1H), 8.19 (m, 1H), 8.52 (br s, 2H),8.55 (m, 1H). Microanalysis: Found: C, 57.01; H, 5.08; N, 11.94.C₂₁H₂₂Cl₂N₄O₂ requires C, 58.21; H, 5.12; N, 12.03%. 18

m/z [MH⁺] 434 ¹H-NMR (400 MHz, CDCl₃): δ = 1.08 (t, 3H), 1.18 (t, 3H),2.42 (q, 2H), 2.52 (q, 2H), 3.96 (m, 2H), 4.24 (t, 2H), 6.79 (s, 2H),7.01 (s, 1H), 8.22 (br s, 1H), 8.54 (d, 1H), 8.78 (d, 1H), 9.40 (s, 1H).

EXAMPLE 193-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}benzonitrile

A mixture of the chloroketone of Preparation 2 (243 mg, 1.50 mmol),3-cyanophenol (155 mg, 1.50 mmol), cesium carbonate (488 mg, 1.50 mmol)and acetone (10 ml) was heated under reflux for 2 hours. After cooling,the solid was removed by filtration and the filtrate was concentratedunder reduced pressure to leave a brown oil. The oil was dissolved inethanol (10 ml), hydroxyethylhydrazine (114 mg, 1.50 mmol) was added andthe mixture was heated at 60° C. for 18 hours. After cooling, themixture was concentrated under reduced pressure. A solution of theresidue in dichloromethane (10 ml) was washed with 2M aqueoushydrochloric acid (5 ml) and water (5 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure to leave ayellow oil. The crude product was purified by flash columnchromatography on silica gel eluting with ethyl acetate to provide thetitle compound (80 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.40 (q, 2H), 2.50 (q, 2H),3.68 (br s, 1H), 4.07 (m, 4H), 7.12 (s, 1H), 7.14 (d, 1H), 7.28 (d, 2H).

LRMS (electrospray): m/z [MH⁺] 286; [MNa⁺] 308.

EXAMPLES 20 TO 38

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 19 using theappropriate phenols and the chloroketone of Preparation 2.

LRMS Example No. R⁴ (electrospray) Analytical Data 20

m/z [MH⁺] 314. ¹H-NMR (400 MHz, CDCl₃): δ = 0.99 (t, 3H), 1.09 (t, 3H),2.18 (s, 6H), 2.25 (q, 2H), 2.40 (q, 2H), 3.78 (br s, 1H), 4.00 (m, 4H),7.34 (s, 2H). 21

m/z [MH⁺] 320. ¹H-NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6H), 2.40 (q, 2H),2.53 (q, 2H), 3.56 (br s, 1H), 4.04 (m, 2H), 4.08 (m, 2H), 6.80 (d, 1H),7.44 (d, 1H), 7.72 (s, 1H). Accurate Mass: Found: 320.1165 [MH⁺;C₁₆H₁₈CIN₃O₂ requires 320.1161 [MH⁺]. 22

m/z [MH⁺] 304. ¹H-NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6H), 2.39 (q, 2H),2.50 (q, 2H), 4.60 (m, 4H), 7.05 (m, 1H), 7.14 (m, 2H). 23

m/z [MH⁺] 295. ¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (m, 6H), 2.41 (m, 2H),2.51 (m, 2H), 3.78 (br s, 1H), 4.06 (m, 4H), 6.81 (m, 2H), 7.21 (m, 2H).Micro- analysis: Found: C, 60.88; H, 6.49; N, 9.40. C₁₅H₁₉CIN₂O₂requires C, 61.12; H, 6.50; N, 9.50%. 24

m/z [MH⁺] 295. ¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (t, 3H), 1.14 (t, 3H),2.41, (q, 2H), 2.52 (q, 2H), 3.79 (br s, 1H), 4.05 (m, 4H), 6.78 (d,1H), 6.58 (s, 1H), 6.98 (d, 1H), 7.19 (t, 1H). 25

m/z [MH⁺] 295. ¹H-NMR (400 MHz, CDCl₃): δ = 1.08 (t, 3H), 1.15 (t, 3H),2.44 (q, 2H), 2.54 (q, 2H), 4.02 (m, 2H), 4.09 (m, 2H), 6.69 (d, 1H),6.94 (t, 1H), 7.10 (t, 1H), 7.40 (d, 1H). 26

m/z [MH⁺] 329. ¹H-NMR (400 MHz, CDCl₃): δ = 1.01 (t, 3H), 1.10 (t, 3H),2.38 (q, 2H), 2.49 (q, 2H), 3.84 (br s, 1H), 3.99 (m, 4H), 7.01 (t, 1H),7.30 (d, 2H). Accurate Mass: Found: 329.0822 [MH⁺]; C₁₅H₁₈Cl₂N₂O₂requires 329.0818 27

m/z [M - (H⁺)] 328. ¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (t, 3H), 1.14 (t,3H), 2.41 (q, 2H), 2.51 (q, 2H), 4.03 (m, 2H), 4.07 (m, 2H), 6.60 (d,1H), 7.04 (1, 1H), 7.10 (t, 1H). 28

m/z [MH⁺] 329. ¹H-NMR (400 MHz, CDCl₃): δ = 1.08 (t, 3H), 1.14 (t, 3H),2.41 (q, 2H), 2.51 (q, 2H), 4.03 (m, 2H), 4.08 (m, 2H), 6.62 (d, 1H),7.09 (d, 1H). Microanalysis: Found: C, 54.66; H, 5.54; N, 8.12.C₁₅H₁₈Cl₂N₂O₂ requires C, 54.72; H, 5.51; N, 8.51%. 29

m/z [MH⁺] 279. ¹H-NMR (400 MHz, CDCl₃): δ = 1.10 (t, 3H), 1.14 (1, 3H),2.44 (q, 2H), 2.55 (q, 2H), 3.79 (br s, 1H), 4.06 (m, 4H), 6.71 (m, 1H),6.98 (m, 2H), 7.12 (m, 1H). 30

m/z [MH⁺] 279. ¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (t, 3H), 1.12 (t, 3H),2.43 (q, 2H), 2.52 (q, 2H), 3.78 (br s, 1H), 4.04 (m, 4H), 6.59 (m, 1H),6.75 (m, 2H), 7.20 (m, 2H). 31

m/z [MH⁺] 289. ¹H-NMR (400 MHz, CDCl₃): δ = 1.10 (t, 3H), 1.17 (t, 3H),2.25 (s, 6H), 2.42 (q, 2H), 2.52 (q, 2H), 3.90 (br s, 1H), 4.05 (m, 4H),6.49 (s, 2H), 6.62 (s, 1H). 32

m/z [MH⁺] 293. ¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (t, 3H), 1.14 (t, 3H),2.22 (s, 3H), 2.42 (q, 2H), 2.31 (q, 2H), 3.83 (br s, 1H), 4.03 (m, 4H),6.60 (m, 1H), 6.70 (m, 1H), 6.88 (m,1H). 33

m/z [MH⁺] 329. ¹H-NMR (400 MHz, CDCl₃): δ = 1.11 (t, 3H), 1.17 (t, 3H),2.42 (q, 2H), 2.54 (q, 2H), 4.06 (m, 4H), 6.69 (s, 1H), 6.94 (d, 1H),7.34 (d, 1H). Microanalysis: Found: C, 54.84; H, 5.67; N, 8.48.C₁₅H₁₈Cl₂N₂O₂ requires C, 54.72; H, 5.51; N, 8.51%. 34

m/z [MH⁺] 297. ¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (3, 3H), 1.12 (t, 3H),2.42 (q, 2H), 2.50 (q, 2H), 3.68 (br s, 1H), 4.01 (m, 4H), 6.47 (m, 1H),6.77 (m, 1H), 6.86 (m, 1H). Microanalysis: Found: C, 60.57; H, 6.23; N,9.52. C₁₅H₁₈F₂N₂O₂ requires C, 60.80; H, 6.12; N, 9.45%. 35

m/z [MH⁺] 329. ¹H-NMR (400 MHz, CDCl₃): δ = 1.08 (t, 3H), 1.12 (t, 3H),2.41 (q, 2H), 2.51 (q, 2H), 3.73 (br s, 1 H), 4.08 (m, 4H), 6.75 (d,1H), 6.98 (s, 1H), 7.31 (d, 1H). Microanalysis: Found: C, 54.70; H,5.54; N, 8.50. C₁₅H₁₈C₁₂N₂O₂ requires C, 54.72; H, 5.51; N, 8.51%. 36

m/z [MH⁺] 297. ¹H-NMR (400 MHz, CDCl₃): δ = 1.08 (t, 3H), 1.12 (t, 3H),2.49 (q, 2H), 2.60 (q, 2H), 3.81 (br s, 1H), 3.99 (m, 4H), 6.91 (m, 2H),6.99 (m, 1 H). 37

m/z [MH⁺] 297. ¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (t, 3H), 1.15 (t, 3H),2.45 (q, 2H), 2.55 (q, 2H), 3.70 (br s, 1H), 4.06 (m, 4H), 6.46 (m, 1H),6.62 (m, 1H), 7.08 (m, 1H). 38

m/z [MH⁺] 297. ¹H-NMR (400 MHz, CDCl₃): δ = 1.08 (t, 3H), 1.14 (t, 3H),2.41 (q, 2H), 2.53 (q, 2H), 3.72 (br s, 1H), 4.05 (m, 4H), 6.43 (m, 3H).

EXAMPLE 394-(3,5-Dichlorophenoxy)-3,5-diethyl-1-(2-methoxyethyl)-1H-pyrazole

Sodium hydride (60% dispersion in oil, 34 mg, 0.850 mmol) was added to astirred solution of 4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole ofExample 3 (200 mg, 0.701 mmol) and methoxyethyl bromide (117 mg, 0.850mmol) in dry N,N-dimethylformamide (2 ml) at 0° C. under nitrogen. Themixture was stirred at 0° C. for 45 minutes during which time hydrogenwas evolved and the yellow solution turned dark brown. The reactionmixture was quenched by the addition of water (5 ml) and the mixtureconcentrated under reduced pressure. The residue was dissolved in ethylacetate (20 ml) and washed with water (10 ml) and brine (10 ml) and thendried over magnesium sulphate, filtered and concentrated under reducedpressure to leave a brown oil. The crude product was purified by flashcolumn chromatography on silica gel eluting with pentane:diethyl ether(80:20, by volume) to provide the title compound (140 mg) as acolourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=1.09-1.15 (m, 6H), 2.41-2.49 (q, 2H),2.51-2.57 (q, 2H), 3.34 (s, 3H), 3.74-3.78 (t, 2H), 4.15-4.17 (t, 2H),6.81 (s, 2H), 7.01 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 343.

Microanalysis: Found: C, 56.25; H, 5.94; N, 7.95. C₁₆H₂₀Cl₂N₂O₂ requiresC, 55.99; H, 5.87; N, 8.16%.

EXAMPLES 40 AND 41

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 39 using theappropriate halides and the pyrazole of Example 3.

LRMS Example No. R² (thermospray) Analytical Data 40

m/z [MH⁺] 329. ¹H-NMR (300 MHz, CDCl₃): δ = 1.13 − 1.18 (m, 6 H), 2.45(q, 2 H), 2.60 (q, 2 H), 3.37 (s, 3 H), 5.34 (s, 2 H), 6.80 (s, 2 H),7.02 (s, 1 H). Microanalysis: Found: C, 54.72; H, 5.46; N, 8.40.C₁₅H₁₈Cl₂N₂O₂ requires C, 54.72; H, 5.51; N, 8.51%. 41

m/z [MH⁺] 299. ¹H-NMR (300 MHz, CDCl₃): δ = 1.15 (m, 6 H), 2.48 (m, 4H), 3.79 (s, 3 H), 6.82 (s, 2 H), 7.01 (s, 1 H). Microanalysis: Found:C, 56.08; H, 5.37; N, 9.29. C₁₄H₁₈Cl₂N₂O requires C, 56.20; H, 5.39; N,9.36%.

EXAMPLE 42 4-(3,5-Dichlorophenoxy)-3-ethyl-1H-pyrazole

A solution of the enamine of Preparation 6 (2.88 g, 10.0 mmol) andhydrazine hydrate (0.49 ml, 10.0 mmol) in ethanol (10 ml) was heatedunder reflux for 12 hours. After cooling further hydrazine hydrate (0.49ml, 10.0 mmol) was added and the reaction was heated under reflux for 3hours. After cooling the mixture was concentrated under reduced pressureand the residue was purified by flash column chromatography on silicagel eluting with cyclohexane:ethyl acetate (80:20, by volume) and thencyclohexane:ethyl acetate (60:40, by volume) to provide the titlecompound (620 mg) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.23 (t, 3H), 2.66 (q, 2H), 6.87 (s, 2H),7.02 (s, 1H), 7.40 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 257; [M-(H⁺)] 255.

EXAMPLE 434-{2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl}morpholine

Osmium tetroxide (1.00 ml of a 2.5% w/v solution in tert-butanol) wasadded dropwise to a stirred solution of the pyrazole of Example 64 (3.00g, 9.23 mmol) and sodium periodate (4.93 g, 23.1 mmol) in acetone (90ml) and water (30 ml) at room temperature. A white precipitate formedafter 5 minutes and the suspension was stirred for a further 3 hours.The solid was removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was partitioned between ethylacetate (300 ml) and water (100 ml) and the organic phase was separated,dried over magnesium sulphate, filtered and concentrated under reducedpressure to yield an intermediate aldehyde. An aliquot of the aldehyde(100 mg, 0.305 mmol) was dissolved in dichloromethane (5 ml) andmorpholine (30 mg, 0.344 mmol) and glacial acetic acid (17.1 μL, 0.305mmol) were added. After stirring at room temperature for 5 minutessodium triacetoxyborohydride (95 mg, 0.451 mmol) was added in oneportion and the reaction was stirred for 1 hour. After this time theresultant mixture was diluted with dichloromethane (20 ml) andpartitioned between water (30 ml) and dichloromethane (20 ml). Theorganic phase was washed with 2M aqueous sodium hydroxide solution (10ml), dried over magnesium sulphate, filtered and concentrated underreduced pressure. The crude product was purified by flash chromatographyon silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, byvolume) to provide the title compound (125 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.06 (m, 6H), 2.12 (m, 8H), 2.75 (t, 2H),3.64 (m, 4H), 4.04 (t, 2H), 6.73 (s, 2H), 6.95 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 398.

Microanalysis: Found: C, 57.18; H, 6.31; N, 10.36. C₁₉H₂₅Cl₂N₃O₂requires C, 57.29; H, 6.33; N, 10.55%.

EXAMPLES 44 TO 49

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 43 using theappropriate amine starting material and the pyrazole of Example 64.

LRMS Example No. R (thermospray) Analytical Data 44

m/z [MH⁺] 386. ¹H-NMR (300 MHz, CDCl₃): δ = 1.09-1.17 (m, 6 H), 2.40-2.47 (q, 2 H), 2.50-2.56 (q, 2 H), 2.80-2.52 (t, 2 H), 3.07- 3.11 (t, 2H), 3.36 (s, 3 H), 3.47-3.51 (t, 2 H), 4.09-4.11 (t, 2 H), 6.81 (s, 2H), 7.01 (s, 1 H). 45

m/z [MH⁺] 439. ¹H-NMR (400 MHz, CDCl₃): δ = 1.04 (m, 6 H), 2.00 (s, 3H), 2.38 (m, 6 H), 2.44 (q, 2 H), 2.77 (q, 2 H), 3.38 (m, 2 H), 3.55 (m,2 H), 4.05 (m, 2 H), 6.71 (s, 2 H), 6.92 (s, 1 H). 46

m/z [MH⁺] 356. ¹H-NMR (400 MHz, CDCl₃): δ = 1.05 (m, 6 H), 2.23 (s, 6H), 2.38 (q, 2 H), 2.45 (q, 2 H), 2.69 (m, 2 H), 4.03 (m, 2 H), 6.75 (s,2 H), 6.95 (s, 1 H). 47

m/z [MH⁺] 413. ¹H-NMR (400 MHz, CDCl₃): δ = 1.08 (m, 6 H), 1.59 (br s, 1H), 1.91 (s, 3 H), 2.38 (q, 2 H), 2.48 (q, 2 H), 2.71 (m, 2 H), 2.99 (m,2 H), 3.28 (m, 2 H), 4.02 (m, 2 H), 6.09 (br s, 1 H), 6.71 (s, 2 H),6.95 (s, 1 H). Microanalysis: Found: C, 54.86; H, 6.32; N, 13.33.C₁₉H₂₆Cl₂N₄O₂ requires C, 55.21; H, 6.34; N, 13.55%. m.p. 69-70° C. 48

m/z [MH⁺] 342. ¹H-NMR (400 MHz, CDCl₃): δ = 1.08 (m, 7 H), 2.39 (m, 2H), 2.42 (s, 3 H), 2.49 (q, 2 H), 3.00 (m, 2 H), 4.05 (m, 2 H), 6.78 (s,2 H), 6.96 (s, 1 H). 49

m/z [MH⁺] 412. ¹H-NMR (400 MHz, CDCl₃): δ = 1.05 (m, 6 H), 1.49 (m, 1H), 1.81 (m, 4 H), 2.42 (q, 2 H), 2.52 (q, 2 H), 2.64 (m, 2 H), 3.08 (t,2 H), 3.76 (m, 1 H), 3.79 (m, 1 H), 4.00 (m, 1 H), 6.78 (s, 2 H), 6.98(s, 1 H). Microanalysis: Found: C, 57.78; H, 6.68; N, 9.90.C₂₀H₂₇Cl₂N₃O₂ requires C, 58.13; H, 6.61; N, 10.17%.

EXAMPLE 503-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]methyl}morpholine

Sodium hydride (60% dispersion in oil, 37 mg, 0.925 mmol) was added to astirred solution of the mesylate of Preparation 11 (273 mg, 0.925 mmol)and the pyrazole of Example 3 (220 mg, 0.772 mmol) in dryN,N-dimethylformamide (4 ml) at 0° C. under nitrogen. The mixture washeated at 50° C. for 3 hours during which time the yellow solutionturned dark brown. The reaction mixture was quenched by the addition ofwater (5 ml) and the mixture was concentrated under reduced pressure. Asolution of the residue in ethyl acetate (20 ml) was washed with water(10 ml) and brine (10 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure to leave a brown oil. The oil wasdissolved in dichloromethane (3 ml), trifluoroacetic acid (1 ml) wasadded and the reaction was stirred at room temperature for 12 hours. Themixture was concentrated under reduced pressure and the residue wasdissolved in ethyl acetate (10 ml) and washed with 1M aqueoushydrochloric acid (2×5 ml). The combined aqueous phases were neutralisedwith solid sodium carbonate and extracted with ethyl acetate (3×20 ml).The combined ethyl acetate layers were dried over magnesium sulphate,filtered and concentrated under reduced pressure. The crude product waspurified by flash column chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (3 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.15 (m, 6H), 2.41 (q, 2H), 2.51 (q, 2H),2.89 (m, 2H), 3.30 (m, 2H), 3.58 (m, 1H), 3.78 (m, 2H), 3.87 (d, 2H),6.88 (s, 2H), 7.00 (1H, s).

LRMS (thermospray): m/z [MH⁺] 384.

EXAMPLE 511-(3-Azetidinyl)-4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole

Sodium hydride (60% dispersion in oil, 30 mg, 0.750 mmol) was added to astirred solution of the pyrazole of Example 3 (200 mg, 0.702 mmol) and1-benzhydryl-3-azetidinyl methanesulfonate (222 mg, 0.702 mmol) (see J.Org. Chem., 1972, 37, 3953) in N,N-dimethylformamide (5 ml) at 0° C.under nitrogen. The mixture was heated at 50° C. for 4 hours and thencooled to room temperature. The reaction mixture was quenched by theaddition of water (30 ml) and the aqueous mixture was extracted withether (2×50 ml). The combined organic phases were washed with water (10ml) and brine (10 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure to leave a brown oil. The oil waspurified by flash column chromatography on silica gel eluting withdichloromethane to provide the intermediate (60 mg) as a yellow oil. Theoil was dissolved in dichloromethane (5 ml) and1-chloroethylchloroformate (20 μL, 0.182 mmol) was added at roomtemperature under nitrogen. The mixture was heated under reflux for 4hours, cooled to room temperature and concentrated under reducedpressure to leave a yellow oil. The oil was dissolved in methanol (5 ml)and the resulting solution was heated under reflux for 1 hour, cooled toroom temperature and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography on silica geleluting with dichloromethane:methanol:ammonia (95:4:1, by volume) toprovide the title compound (17 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.08 (t, 3H), 1.16 (t, 3H), 2.48 (m, 4H),3.87 (t, 2H), 4.40 (t, 2H), 5.07 (q, 1H), 6.79 (s, 2H), 7.01 (m, 1H).

LRMS (thermospray): m/z [MH⁺] 340.

EXAMPLE 527-(3,5-Dichlorophenoxy)-6-ethyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazole

The triflate of Preparation 15 (282 mg, 0.500 mmol), tributylvinyltin(175 μL, 0.600 mmol), palladium dibenzylidene acetone (23 mg, 0.025mmol), triphenyl arsine (12 mg, 0.040 mmol) and lithium chloride (64 mg,1.50 mmol) were heated in N,N-dimethylformamide (3 ml) at 80° C. undernitrogen for 12 hours. The reaction was cooled to room temperature andpartitioned between water (20 ml) and ethyl acetate (20 ml). The organiclayer was washed with brine (10 ml), dried over magnesium sulphate,filtered and concentrated under reduced pressure. The crude product waspurified by flash column chromatography on silica gel eluting withpentane:ethyl acetate (90:10, by volume) to provide the title compound(34 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.16 (t, 3H), 2.45 (q, 2H), 4.29 (t, 2H),5.03 (t, 2H), 6.89 (s, 2H), 7.02 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 299.

EXAMPLE 53 4-(3,5-Dichlorophenoxy)-3,5-dimethyl-1H-pyrazole

A mixture of 3-chloro-2,4-pentanedione (5.00 g, 37.0 mmol),3,5-dichlorophenol (6.03 g, 37.0 mmol), cesium carbonate (12.0 g, 37.0mmol) and acetone (40 ml) was heated under reflux for 18 hours. Aftercooling the solid was removed by filtration and the filtrateconcentrated under reduced pressure. The intermediate was dissolved inethanol (30 ml) and hydrazine hydrate (1.85 g, 37.0 mmol) was added andthe mixture heated at 60° C. for 30 minutes. After cooling the mixturewas concentrated under reduced pressure and the residue purified byflash column chromatography on silica gel eluting with ethylacetate:pentane (30:70, by volume) to provide the title compound (3.00g) as a yellow oil which solidified on standing to leave a yellow solid,m.p. 85-87° C.

¹H-NMR (300 MHz, CDCl₃): δ=2.14 (s, 6H), 5.24 (br s, 1H), 6.81 (s, 2H),7.02 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 257.

Microanalysis: Found: C, 49.58; H, 4.06; N, 11.05. C₁₁H₁₀Cl₂N₂O.0.4H₂Orequires C, 49.98; H, 4.12; N. 10.60%.

EXAMPLE 541-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-2-propanol

Osmium tetroxide (1.00 ml of a 2.5% w/v solution in tert-butanol) wasadded dropwise to a stirred solution of the pyrazole of Example 64 (3.00g, 9.23 mmol) and sodium periodate (4.93 g, 23.1 mmol) in acetone (90ml) and water (30 ml) at room temperature. A white precipitate formedafter 5 minutes and the suspension was stirred for a further 3 hours.The solid was removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was partitioned between ethylacetate (300 ml) and water (100 ml) and the organic phase was separated,dried over magnesium sulphate, filtered and concentrated under reducedpressure to yield the intermediate aldehyde. An aliquot of the aldehyde(250 mg, 0.765 mmol) was dissolved in tetrahydrofuran (5 ml) and storedunder nitrogen. In a separate flask, anhydrous cerium trichloride (377mg, 1.53 mmol) was added to a stirred solution of methyl magnesiumbromide (0.51 ml of a 3M solution in ether, 1.53 mmol) intetrahydrofuran (5 ml) at room temperature under nitrogen. The mixturewas stirred at room temperature for 1.5 hours and the aldehyde intetrahydrofuran was added dropwise. The mixture was stirred for 12 hoursand the reaction was then quenched with 1M aqueous acetic acid at roomtemperature. The mixture was diluted with dichloromethane (20 ml),washed with water (5 ml) and brine (5 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography on silica geleluting with pentane:ethyl acetate (70:30, by volume) to provide thetitle compound (30 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.05 (t, 3H), 1.10 (t, 3H), 1.21 (d, 2H),2.40 (q, 2H), 2.47 (q, 2H), 3.79 (dd, 1H), 3.97 (dd, 1H), 4.24 (s, 1H),6.76 (s, 2H), 6.98 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 343.

EXAMPLE 552-{2-[4-(3,5-Dichlorophenxoy)-3,5-diethyl-1-pyrazol-1-yl}ethoxy]ethanamine

Sodium hydride (60% dispersion in oil, 24 mg, 0.600 mmol) was added to astirred solution of the pyrazole of Example 2 (100 mg, 0.303 mmol) indry N,N-dimethylformamide (4 ml) at 0° C. under nitrogen. The mixturewas stirred at 0° C. for 30 minutes and 2-chloroethylamine hydrochloride(53 mg, 0.455 mmol) was added. The reaction mixture was stirred at 0° C.for 30 minutes and then stirred at room temperature for 30 minutes. Thereaction was cooled to 0° C., further sodium hydride (60% dispersion inoil, 24 mg, 0.600 mmol) and 2-chloroethylamine hydrochloride (53 mg,0.455 mmol) were added and the reaction was stirred for 1 hour. Thereaction was quenched by the addition of water (5 ml) and extracted withether (10 ml). The organic layer was washed with 2M aqueous hydrochloricacid (30 ml). The acid was neutralised with solid sodium carbonate andextracted with ether (3×20 ml). The combined ether layers were driedover magnesium sulphate, filtered and concentrated under reducedpressure. The crude product was purified by flash column chromatographyon silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, byvolume) to provide the title compound (21 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.19 (m, 6H), 2.42 (q, 2H), 2.58 (q, 2H),2.80 (t, 2H), 3.38 (t, 2H), 3.81 (t, 2H), 4.18 (t, 2H), 6.78 (s, 2H),7.02 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 372.

EXAMPLE 564-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}morpholine

Morpholine (140 μL, 1.59 mmol) was added in one portion to a stirredsolution of the bromide of Preparation 8 (200 mg, 0.531 mmol) inisopropanol (4 ml) at room temperature. The mixture was heated at 50° C.for 1 hour, cooled to room temperature and concentrated under reducedpressure to leave a yellow oil. The crude product was purified by flashcolumn chromatography on silica gel eluting with ethyl acetate toprovide the title compound (60 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=2.13 (s, 3H), 2.42 (m, 4H), 3.38 (s, 2H),3.64 (m, 4H), 6.79 (s, 2H), 7.02 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 342.

EXAMPLE 574-(3,5-Dichlorophenoxy)-3-methyl-5-[(2-methyl-1H-imidazol-1-yl)methyl]-1H-pyrazole

Sodium hydride (60% dispersion in oil, 32 mg, 0.800 mmol) was added to astirred solution of 2-methylimidazole (65 mg, 0.800 mmol) inN,N-dimethylformamide (5 ml) at 0° C. under nitrogen. The mixture wasstirred for 10 minutes and then the bromide of Preparation 8 (100 mg,0.261 mmol) was added and the reaction was stirred at room temperaturefor 1 hour. The reaction mixture was quenched by the addition of 1Maqueous sodium hydroxide solution (5 ml) and the mixture wasconcentrated under reduced pressure. A solution of the residue in ethylacetate (20 ml) was washed with water (10 ml) and brine (10 ml), driedover magnesium sulphate, filtered and concentrated under reducedpressure to leave a brown oil. The crude product was purified by flashcolumn chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4.5:0.5, by volume) to provide thetitle compound (10 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.14 (s, 3H), 2.35 (s, 3H), 4.89 (s, 2H),6.68 (s, 2H), 6.78 (s, 1H), 6.82 (s, 1H), 7.03 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 337.

EXAMPLE 582-[4-(3,5-Dichlorophenoxy)-3-ethyl-5-methoxy-1H-pyrazol-1-yl]ethanol

The triflate of Preparation 15 (282 mg, 0.500 mmol) was dissolved inmethanol (3 ml) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)chloride (18 mg, 0.025 mmol) was added in one portion at roomtemperature. The mixture was heated at 50° C. under an atmosphere ofcarbon monoxide (345 kPa, 50 psi) for 10 hours. The reaction was cooledto room temperature and concentrated under reduced pressure to leave abrown oil. The oil was dissolved in a mixture of tetrahydrofuran (0.5ml), glacial acetic acid (1.0 ml) and water (0.5 ml) and stirred at roomtemperature for 12 hours. The solvent was removed under a stream ofnitrogen to leave a yellow solid and the crude product was purified byflash column chromatography on silica gel eluting withdichloromethane:acetonitrile (95:5, by volume) and thendichloromethane:acetonitrile (90:10, by volume) to provide the titlecompound (6 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=1.13 (t, 3H), 2.41 (q, 2H), 3.44 (br s, 1H),3.94 (s, 3H), 4.23 (m, 4H), 6.87 (s, 2H), 7.09 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 331.

EXAMPLE 591-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}-1H-1,2,4-triazole

A suspension of the bromide of Preparation 8 (100 mg, 0.264 mmol),1,2,4-triazole (92 mg, 1.32 mmol) and sodium carbonate (140 mg, 1.32mmol) in toluene (5 ml) was heated at 100° C. for 12 hours. Thesuspension was cooled to room temperature and 1M aqueous sodiumhydroxide solution (5 ml) was added. The mixture was extracted withethyl acetate (3×20 ml) and the combined organic phases were dried overmagnesium sulphate, filtered and concentrated under reduced pressure toleave a clear oil. The crude product was purified by flash columnchromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4.5:0.5, by volume) to provide thetitle compound (62 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.16 (s, 3H), 5.25 (s, 2H), 6.70 (s, 2H),7.04 (s, 1H), 7.89 (s, 1H), 8.04 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 324.

EXAMPLE 60 3-[(3,5-Diethyl-1H-pyrazol-4-yl)oxy]benzonitrile

Hydrazine hydrate (153 μL, 3.14 mmol) was added to a stirred solution ofthe β-diketone of Preparation 9 (771 mg, 3.14 mmol) in ethanol (16 ml)and the resulting solution was heated under reflux for 12 hours. Aftercooling the mixture was concentrated under reduced pressure and theresidue was purified by flash column chromatography on silica geleluting with pentane:ethyl acetate (75:25, by volume) to provide thetitle compound (712 mg) as a yellow solid, m.p. 81-84° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.15 (t, 6H), 2.47 (q, 4H), 7.11 (m, 2H),7.24 (d, 1H), 7.35 (t, 1H).

LRMS (thermospray): m/z [MH⁺] 242.

Microanalysis: Found: C, 69.03; H, 6.43; N, 17.20. C₁₄H₁₅N₃O₃.0.13H₂Orequires C, 69.02; H, 6.31; N, 17.25%.

EXAMPLE 613-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}benzonitrile

The pyrazole of Example 60 (200 mg, 0.829 mmol) and 2-chloroethylaminehydrochloride (144 mg, 1.24 mmol) were heated as a melt at 150° C. for17 hours. After cooling the solid was dissolved in saturated aqueoussodium hydrogencarbonate (15 ml) and extracted with dichloromethane(2×10 ml). The combined organic phases were washed with 2M aqueoushydrochloric acid (20 ml) and the aqueous layer was neutralised withsolid sodium carbonate and extracted with dichloromethane (3×10 ml). Thecombined organic phases were dried over magnesium sulphate, filtered andconcentrated under reduced pressure to leave an orange gum. The crudeproduct was purified by flash column chromatography on silica geleluting with dichloromethane:methanol (90:10) thendichloromethane:methanol:ammonia (90:9:1, by volume) to provide thetitle compound (124 mg) as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.11 (m, 6H), 2.41 (q, 2H), 2.52 (q, 2H),3.18 (t, 2H), 4.04 (t, 2H), 7.15 (m, 2H), 7.29 (d, 1H), 7.38 (t, 1H).

LRMS (thermospray): m/z [MH⁺] 285.

2-[4-(3-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetamide

A saturated solution of ammonia in methanol (2.3 ml) was added to theester of Example 63 (75 mg, 0.229 mmol) in a vial at room temperaturethen the vial was sealed and heated at 75° C. for 17 hours. Aftercooling to room temperature the mixture was concentrated under reducedpressure to leave a cream solid. The crude product was purified by flashcolumn chromatography on silica gel eluting with dichloromethane thendichloromethane:methanol (99:1, by volume) to provide the title compound(49 mg) as a white solid, m.p. 159-160° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (t, 3H), 1.17 (t, 3H), 2.44 (q, 2H),2.53 (q, 2H), 4.69 (s, 2H), 5.44 (br s, 1H), 6.22 (br s, 1H), 7.14 (m,2H), 7.31 (d, 1H), 7.40 (t, 1H).

LRMS (thermospray): m/z [MH⁺] 299.

Microanalysis: Found: C, 64.20; H, 6.12; N, 18.79. C₁₆H₁₈N₄O₂ requiresC, 64.41; H, 6.08; N, 18.78%.

EXAMPLE 63 Ethyl[4-(3-cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetate

A solution of ethylhydrazinoacetate (88 mg, 0.571 mmol) in ethanol (2.0ml) was added to a stirred solution of the β-diketone of Preparation 9(140 mg, 0.571 mmol) and triethylamine (88 μL, 0.628 ml) in ethanol (1.0ml) and the resulting solution was heated under reflux for 18 hours.After cooling, the mixture was concentrated under reduced pressure andthe residue was partitioned between dichloromethane (20 ml) and water(10 ml). The organic layer was separated, washed with brine (10 ml),dried over magnesium sulphate, filtered and concentrated under reducedpressure. The crude product was purified by flash column chromatographyon silica gel eluting with pentane:ethyl acetate (75:25, by volume) andthen ethyl acetate to provide the title compound (131 mg) as a yellowoil.

¹H-NMR (400 MHz, CDCl₃): δ=1.08 (m, 6H), 1.25 (t, 3H), 2.40 (m, 4H),4.20 (q, 2H), 4.77 (s, 2H), 7.12 (m, 2H), 7.23 (d, 1H), 7.34 (t, 1H).

LRMS (thermospray): m/z [MH⁺] 328.

EXAMPLE 64 1-Allyl-4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole

Sodium hydride (60% dispersion in oil, 770 mg, 19.2 mmol) was added to astirred solution of allyl bromide (1.70 ml, 19.2 mmol) and the pyrazoleof Example 3 (5.00 g, 17.5 mmol) in N,N-dimethylformamide (20 ml) at 0°C. under nitrogen. The reaction was warmed to room temperature andstirred for 1 hour. The reaction mixture was quenched by the addition ofwater (100 ml) and the aqueous phase was extracted with ether (2×50 ml).The combined organic phases were washed with water (30 ml) and brine (30ml), dried over magnesium sulphate, filtered and concentrated underreduced pressure to leave a brown oil. The crude product was purified byflash column chromatography on silica gel eluting with pentane:ethylacetate (80:20, by volume) to provide the title compound (5.00 g) as ayellow oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.11 (m, 6H), 2.46 (m, 4H), 4.65 (d, 2H),5.04 (d, 1H), 5.22 (d, 1H), 5.99 (m, 1H), 6.79 (s, 2H), 6.99 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 325.

EXAMPLE 65N-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]-methyl}-N-(4-methoxybenzyl)amine

4-Methoxybenzylamine (0.104 ml, 0.800 mmol) was added in one portion toa stirred solution of the bromide of Preparation 8 (100 mg, 0.265 mmol)in isopropanol (2 ml) at room temperature. The mixture was heated at 50°C. for 1 hour, cooled to room temperature and concentrated under reducedpressure to leave a yellow oil. The oil was diluted with diethyl ether(20 ml), washed with saturated aqueous sodium hydrogen carbonate (5 ml)and water (5 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified byflash column chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (50 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.13 (s, 3H), 3.68 (s, 2H), 3.71 (s, 2H),3.80 (s, 3H), 6.83 (m, 4H), 7.03 (s, 1H), 7.17 (m, 2H).

LRMS (thermospray): m/z [MH⁺] 392.

EXAMPLES 66 TO 75

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 65 using theappropriate amine starting material and the bromide of Preparation 8.

LRMS Example No. R (thermospray) Analytical Data 66

m/z [MH⁺] 326. ¹H-NMR (300 MHz, CDCl₃): δ = 0.09 (m, 2 H), 0.49 (q, 2H), 0.90 (m, 1 H), 2.34 (s, 3 H), 2.47 (d, 2 H), 3.73 (s, 2 H), 6.82 (s,2 H), 7.03 (s, 1 H). 67

m/z [MH⁺] 300. ¹H-NMR (400 MHz, CDCl₃): δ = 2.08 (s, 3 H), 2.20 (s, 6H), 3.31 (s, 2 H), 6.76 (s, 2 H), 6.97 (s, 1 H). 68

m/z [MH⁺] 286. ¹H-NMR (400 MHz, CDCl₃): δ = 2.12 (s, 3 H), 2.42 (s, 3H), 3.65 (s, 2 H), 6.80 (s, 2 H), 7.02 (s, 1 H). 69

m/z [MH⁺] 355. ¹H-NMR (400 MHz, CDCl₃): δ = 2.08 (s, 3 H), 2.22 (s, 3H), 2.31 (m, 8 H), 3.36 (s, 2 H), 6.76 (s, 2 H), 6.97 (s, 1 H). 70

m/z [MH⁺] 385. ¹H-NMR (400 MHz, CDCl₃): δ = 1.50 (m, 2 H), 1.60 (m, 2H), 1.90 (m, 4 H), 2.41 (m, 2 H), 3.25 (s, 2 H), 3.75 (m, 2 H), 5.52 (s,1 H), 5.80 (s, 1 H), 6.67 (s, 2 H), 6.86 (s, 1 H). 71

m/z [MH⁺] 330. ¹H-NMR (400 MHz, CDCl₃): δ = 2.08 (s, 3 H), 2.74 (m, 2H), 3.30 (s, 3 H), 3.44 (m, 2 H), 3.68 (s, 2 H), 6.76 (s, 2 H), 6.98 (s,1 H). 72

m/z [MH⁺] 383. ¹H-NMR (400 MHz, CDCl₃): δ = 2.02 (s, 3 H), 2.10 (s, 3H), 2.38 (m, 4 H), 3.34 (m, 2 H), 3.38 (s, 2 H), 3.51 (m, 2 H), 6.76 (s,2 H), 6.98 (s, 1 H). 73

m/z [MH⁺] 357. ¹H-NMR (400 MHz, CDCl₃): δ = 1.92 (s, 3 H), 2.09 (s, 3H), 2.70 (m, 2 H), 3.29 (m, 2 H), 3.65 (s, 2 H), 6.01 (s, 1 H), 6.76 (s,2 H), 6.99 (s, 1 H). 74

m/z [MH⁺] 397. ¹H-NMR (400 MHz, CDCl₃): δ = 1.30 (m, 2 H), 1.80 (m, 2H), 1.92 (s, 3 H), 2.09 (m, 5 H), 2.70 (m, 2 H), 3.34 (s, 2 H), 3.71 (m,1 H), 6.78 (s, 2 H), 6.98 (s, 1 H). 75

m/z [MH⁺] 370. ¹H-NMR (300 MHZ, CDCl₃): δ = 1.60 (m, 2 H), 1.80 (m, 2H), 2.13 (s, 3 H), 2.20 (m, 2 H), 2.71 (m, 2 H), 3.22 (m, 1 H), 3.33 (s,3 H), 3.39 (s, 2 H), 6.81 (s, 2 H), 7.03 (s, 1 H).

EXAMPLE 76 3-Chloro-5-[(3,5-dimethyl-1H-pyrazol-4-yl)oxy]benzonitrile

Hydrazine hydrate (1.10 ml, 21.9 mol) was added to a stirred solution ofthe β-diketone of Preparation 16 (5.50 g, 21.9 mmol) in glacial aceticacid (22 ml) and the resulting solution was stirred at room temperaturefor 14 hours. The mixture was concentrated under reduced pressure andthe residue was purified by flash column chromatography on silica geleluting with dichloromethane and then dichloromethane:ethyl acetate(85:15, by volume) to provide the title compound (4.80 g) as a yellowsolid, m.p. 136-140° C.

¹H-NMR (400 MHz, CDCl₃): δ=2.09 (s, 6H), 7.02 (m, 1H), 7.10 (m, 1H),7.25 (m, 1H).

LRMS (electrospray): m/z [MH⁺] 248.

Microanalysis: Found: C, 57.91; H, 4.03; N, 16.79. C₁₂H₁₀N₃OCl requiresC, 58.19; H, 4.07; N, 16.97%.

EXAMPLE 773-{[5-(Aminomethyl)-3-methyl-1H-pyrazol-4-yl]oxy}-5-chlorobenzonitrile

The bromide of Preparation 18 (300 mg, 0.800 mmol) was added to asaturated solution of ammonia in isopropanol (50 ml) at 0° C. Thereaction was stirred for 2 hours and allowed to slowly warm to roomtemperature. The mixture was concentrated under reduced pressure and theresulting yellow oil was dissolved in dichloromethane (50 ml). Thedichloromethane solution was washed with 1M aqueous sodium carbonatesolution (20 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure to provide the title compound (220mg) as a white foam.

¹H-NMR (300 MHz, CDCl₃): δ=2.14 (s, 3H), 3.79 (s, 2H), 7.08 (1H, s),7.16 (1H, s), 7.31 (1H, s).

LRMS (thermospray): m/z [MH⁺] 263.

EXAMPLE 783-Chloro-5-{[3-methyl-5-(1-piperazinylmethyl)-1H-pyrazol-4-yl]oxy}benzonitrile

t-Butyl-1-piperazinecarboxylate (1.17 g, 6.30 mmol) was added in oneportion to a stirred solution of the bromide of Preparation 18 (500 mg,1.40 mmol) in isopropanol (20 ml) at room temperature. The mixture washeated at 60° C. for 1 hour, cooled to room temperature and concentratedunder reduced pressure to leave a yellow oil. The oil was dissolved indichloromethane (100 ml) and the resulting solution was washed with 1Maqueous sodium carbonate (20 ml) and brine (20 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography on silica geleluting with dichloromethane:methanol:ammonia (95:4:1, by volume) toprovide a yellow foam. The foam was dissolved in dichloromethane (10ml), the resulting solution was cooled to 0° C. and trifluoroacetic acid(2 ml) was added. The reaction was allowed to warm to room temperatureand stirred for 24 hours. The mixture was diluted with dichloromethane(50 ml), washed with 1M aqueous sodium carbonate (20 ml) and brine (20ml), dried over magnesium sulphate, filtered and concentrated underreduced pressure. The crude product was purified by flash columnchromatography on silica gel eluting withdichloromethane:methanol:ammonia (90:9:1, by volume) to provide thetitle compound (400 mg) as a white foam.

¹H-NMR (300 MHz, CDCl₃): δ=2.14 (s, 3H), 2.40 (m, 4H), 2.83 (m, 4H),3.38 (s, 2H), 7.09 (s, 1H), 7.16 (s, 1H), 7.30 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 332.

EXAMPLE 793-Chloro-5-[(5-{[(4-cyanobenzyl)amino]methyl}-3-methyl-1H-pyrazol-4-yl)oxy]benzonitrile

A mixture of 4-cyanobenzaldehyde (60 mg, 0.460 mmol), the amine ofExample 77 (120 mg, 0.460 mmol), magnesium sulphate (500 mg) anddichloromethane (5 ml) was stirred under nitrogen at room temperaturefor 3 days. The mixture was concentrated under reduced pressure and thecrude product was purified by flash column chromatography on silica geleluting with methanol:ethyl acetate (5:95, by volume) to provide a foam.The foam was dissolved in methanol (5 ml), sodium borohydride (50 mg,1.31 mmol) was added in one portion at room temperature and the reactionwas stirred for 30 minutes. The mixture was concentrated under reducedpressure and the residue was dissolved in dichloromethane (20 ml). Theresulting solution was washed with 1M aqueous sodium carbonate solution(10 ml) and brine (10 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified byflash column chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (35 mg) as a white foam.

¹H-NMR (300 MHz, CDCl₃): δ=2.15 (s, 3H), 3.69 (s, 2H), 3.84 (s, 2H),7.06 (s, 1H), 7.15 (s, 1H), 7.31 (s, 1H), 7.38 (d, 2H), 7.60 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 378.

EXAMPLE 803-Chloro-5-[(3-methyl-5-{[4-(methylsulfonyl)-1-piperazinyl]methyl}-1H-pyrazol-4-yl)oxy]benzonitrile

Methanesulphonyl chloride (19 μl, 0.240 mmol) was added dropwise to astirred solution of the amine of Example 78 (80 mg, 0.240 mmol) andtriethylamine (45 μL, 0.288 mmol) in dichloromethane (3 ml) at roomtemperature under nitrogen. The reaction was stirred for 30 minutes andthen concentrated under reduced pressure to leave a yellow oil. Thecrude product was purified by flash column chromatography on silica geleluting with dichloromethane and then dichloromethane:methanol:ammonia(95:4:1, by volume) to provide the title compound (65 mg) as a whitefoam.

¹H-NMR (400 MHz, CDCl₃): δ=2.14 (s, 3H), 2.51 (m, 4H), 2.72 (s, 3H),3.12 (m, 4H), 3.39 (s, 2H), 7.08 (m, 1H), 7.13 (m, 1H), 7.26 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 410.

EXAMPLE 813-Chloro-5-[(5-{[4-(methoxyacetyl)-1-piperazinyl]methyl}-3-methyl-1H-pyrazol-4-yl)oxy]benzonitrile

N-Benzyl-N-cyclohexylcarbodiimide polymer bound (624 mg of 1.3 mmol/g,0.480 mmol) was added in one portion to a stirred solution ofmethoxyacetic acid (37 μL, 0.480 mmol) and the amine of Example 78 (80mg, 0.240 mmol) in dichloromethane (5 ml) at room temperature undernitrogen. The reaction was stirred for 1 hour and the polymer boundreagent was removed by filtration. The filtrate was concentrated underreduced pressure and the crude product was purified by flash columnchromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (45 mg) as a white foam.

¹H-NMR (400 MHz, CDCl₃): δ=2.11 (s, 3H), 2.38 (m, 4H), 3.37 (m, 7H),3.51 (m, 2H), 4.04 (s, 2H), 7.04 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H).

LRMS (thermospray): m/z [MH⁺] 404.

EXAMPLE 82 Methyl4-{[4-(3-chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}-1-piperazinecarboxylate

Methyl chloroformate (19 μl, 0.240 mmol) was added dropwise to a stirredsolution of the amine of Example 78 (80 mg, 0.240 mmol) andtriethylamine (45 μl, 0.288 mmol) in dichloromethane (5 ml) at roomtemperature under nitrogen. The reaction was stirred for 90 minutes andthen concentrated under reduced pressure to leave a yellow oil. Thecrude product was purified by flash column chromatography on silica geleluting with dichloromethane and then dichloromethane:methanol:ammonia(95:4:1, by volume) to provide the title compound (55 mg) as a whitefoam.

¹H-NMR (400 MHz, CDCl₃): δ=2.09 (s, 3H), 2.34 (m, 4H), 3.36 (m, 6H),3.64 (s, 3H), 7.02 (m, 1H), 7.10 (m, 1H), 7.25 (m, 1H).

LRMS (thermospray): m/z [MH⁺] 390.

EXAMPLE 834-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}amino)methyl]benzenesulfonamide

Triethylamine (125 μl, 0.860 mmol) was added in one portion to a stirredsuspension of 4-aminomethylbenzenesulphonamide hydrochloride (144 mg,0.590 mmol) and the bromide of Preparation 18 (100 mg, 0.270 mmol) inisopropanol (5 ml) at room temperature under nitrogen. The reaction was,heated at 70° C. for 1 hour and then cooled to room temperature. Themixture was concentrated under reduced pressure and the crude productwas purified by flash column chromatography on silica gel eluting withdichloromethane and then dichloromethane:methanol:ammonia (90:9:1, byvolume) to provide a foam. The foam was further purified using aPhenomenex Luna C18 column eluting with diethylamine:methanol (0.1:99.1,by volume) to provide the title compound (8 mg) as a white foam.

¹H-NMR (400 MHz, CD₃OD): δ=2.06 (s, 3H), 3.27 (s, 2H), 3.62 (s, 2H),3.79 (s, 2H), 7.17 (s, 1H), 7.21 (s, 1H), 7.40 (m, 3H), 7.77 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 432.

EXAMPLE 844-(3,5-Dichlorophenoxy)-5-(methoxymethyl)-3-methyl-1H-pyrazole

Tetrakis(triphenylphosphine)palladium (60 mg) was added in one portionto a stirred solution of the bromide of Preparation 8 (590 mg, 1.56mmol) in methanol (20 ml) and tetrahydrofuran (20 ml) at roomtemperature. The mixture was heated at 80° C. under an atmosphere ofcarbon monoxide (690 kPa, 100 psi) for 18 hours. The reaction was cooledto room temperature and concentrated under reduced pressure to leave abrown oil. The oil was dissolved in dichloromethane (100 ml) and theresulting solution was washed with water (50 ml), dried over magnesiumsulphate, filtered and evaporated under reduced pressure. The crudeproduct was purified by flash column chromatography on silica geleluting with ether to provide the title compound (110 mg) as acolourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=2.15 (s, 3H), 3.34 (s, 3H), 4.35 (s, 2H),6.83 (s, 2H), 7.03 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 287.

EXAMPLE 85 3-tert-Butyl-4-(3,5-dichlorophenoxy)-5-methyl-1H-pyrazole

A mixture of the dione of Preparation 19 (1.00 g, 5.68 mmol),3,5-dichlorophenol (930 mg, 5.68 mmol), cesium carbonate (1.85 g, 5.68mmol) and acetone (20 ml) was heated at reflux for 18 hours. Aftercooling the solid was removed by filtration and the filtrate wasconcentrated under reduced pressure. The intermediate was dissolved inethanol (20 ml), hydrazine hydrate (284 mg, 5.68 mmol) was added and themixture was heated at 60° C. for 1 hour. After cooling the mixture wasconcentrated under reduced pressure and the residue was purified byflash column chromatography on silica gel eluting with ethylacetate:pentane (25:75, by volume) to provide the title compound (200mg) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.30 (s, 9H), 2.06 (s, 3H), 6.81 (s, 2H),7.02 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 299.

EXAMPLE 86 4-(3,5-Dichlorophenoxy)-3-ethyl-5-methyl-1H-pyrazole

A mixture of the dione of Preparation 50 (4.50 g, 30.8 mmol),3,5-dichlorophenol (5.00 g, 30.8 mmol), caesium carbonate (10.0 g, 30.8mmol) and acetone (40 ml) was heated at reflux for 18 hours. Aftercooling the solid was removed by filtration and the filtrate wasconcentrated under reduced pressure. The intermediate was dissolved inethanol (40 ml), hydrazine hydrate (1.00 ml, 30.8 mmol) was added andthe mixture was heated at 60° C. for 1 hour. After cooling the mixturewas concentrated under reduced pressure and the residue was purified byflash column chromatography on silica gel eluting with ethylacetate:pentane (20:80, by volume) to provide the title compound (1.50g) as an orange oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.18 (t, 3H), 2.11 (s, 3H), 2.53 (q, 2H),6.79 (s, 2H), 7.01 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 271.

EXAMPLE 874-Cyano-N-{[4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}benzamide

1-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide (93 mg, 0.490 mmol) wasadded in one portion to a stirred solution of the amine of Example 109(120 mg, 0.440 mmol) and 4-cyanobenzoic acid (71 mg, 0.490 mmol) indichloromethane (5 ml) at room temperature under nitrogen. The reactionwas stirred for 20 minutes and then washed with 1M aqueous sodiumhydroxide solution (10 ml), 1M aqueous hydrochloric acid (10 ml) andwater (10 ml). The organic layer was dried over magnesium sulphate,filtered and evaporated under reduced pressure to leave a yellow foam.The crude product was purified by flash column chromatography on silicagel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) toprovide the title compound (110 mg) as a white foam.

¹H-NMR (400 MHz, CDCl₃): δ=2.09 (s, 3H), 4.91 (d, 2H), 6.74 (s, 2H),6.95 (s, 1H), 6.98 (d, 1H), 7.65 (d, 2H), 7.77 (d, 2H).

LRMS (thermospray): m/z [MNH₄ ⁺] 418.

EXAMPLE 883-Cyano-N{[4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}benzamide

1-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide (93 mg, 0.490 mmol) wasadded in one portion to a stirred solution of the amine of Example 109(120 mg, 0.440 mmol) and 3-cyanobenzoic acid (71 mg, 0.490 mmol) indichloromethane (5 ml) at room temperature under nitrogen. The reactionwas stirred for 10 minutes and then washed with 1M aqueous sodiumhydroxide solution (10 ml), 1M aqueous hydrochloric acid (10 ml) andbrine (10 ml). The organic layer was dried over magnesium sulphate,filtered and evaporated under reduced pressure to leave a cream foam.The crude product was purified by flash column chromatography on silicagel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) toprovide the title compound (100 mg) as a white foam.

¹H-NMR (400 MHz, CDCl₃): δ=2.14 (s, 3H), 4.53 (d, 2H), 6.78 (s, 2H),6.98 (m, 2H), 7.54 (dd, 1H), 7.76 (d, 1H), 7.95 (d, 1H), 7.99 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 401.

EXAMPLE 89N-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}-N-(3-pyridinylmethyl)amine

A mixture of 3-pyridinecarboxaldehyde (55 mg, 0.514 mmol), the amine ofExample 109 (140 mg, 0.514 mmol), magnesium sulphate (500 mg) anddichloromethane (5 ml) was stirred under nitrogen at room temperaturefor 18 hours. Sodium triacetoxyborohydride (163 mg, 0.771 mmol) wasadded in one portion and then acetic acid (3 drops) was added. After 5minutes the mixture was filtered. The filtrate was washed with 1Maqueous sodium carbonate solution (10 ml), water (10 ml) and brine (10ml), dried over magnesium sulphate, filtered and concentrated underreduced pressure to leave a clear oil. The crude product was purified byflash column chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (60 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=2.09 (s, 3H), 3.66 (s, 2H), 3.74 (s, 2H),6.75 (s, 2H), 6.97 (s, 1H), 7.17 (m, 1H), 7.55 (d, 1H), 8.49 (m, 2H).

LRMS (electrospray): m/z [MH⁺] 363.

EXAMPLE 903-({5-[(4-Acetyl-1-piperazinyl)methyl]-3-methyl-1H-pyrazol-4-yl}oxy)-5-chlorobenzonitrile

N-Acetylpiperazine (104 mg, 0.810 mmol) was added in one portion to astirred solution of the bromide of Preparation 18 (100 mg, 0.271 mmol)in isopropanol (5 ml) at room temperature. The mixture was heated at 50°C. for 1 hour, cooled to room temperature and concentrated under reducedpressure to leave a yellow oil. The crude product was purified by flashcolumn chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (90 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.08 (s, 3H), 2.16 (s, 3H), 2.43 (m, 4H),3.42 (m, 4H), 3.55 (m, 2H), 7.08 (s, 1H), 7.16 (s, 1H), 7.31 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 374.

EXAMPLE 913-Chloro-5-[(5-{[(4-cyanobenzyl)(methyl)amino]methyl}-3-methyl-1H-pyrazol-4-yl)oxy]benzonitrile

The amine of Preparation 20 (127 mg, 0.870 mmol) was added in oneportion to a stirred solution of the bromide of Preparation 18 (100 mg,0.271 mmol) in isopropanol (5 ml) at room temperature. The mixture washeated at 50° C. for 12 hours, cooled to room temperature andconcentrated under reduced pressure to leave a yellow oil. The oil wasdissolved in 1M hydrochloric acid and the aqueous solution was washedwith ethyl acetate (10 ml). Solid sodium carbonate was added untileffervescence ceased and the mixture was extracted with ethyl acetate(3×20 ml). The combined organic phases were dried over magnesiumsulphate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (45 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.14 (s, 3H), 2.17 (s, 3H), 3.45 (s, 2H),3.55 (s, 2H), 7.05 (s, 1H), 7.14 (s, 1H), 7.31 (m, 3H), 7.59 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 392.

EXAMPLE 923-Chloro-5-[(5-{[(4-cyanobenzyl)(2-hydroxyethyl)amino]methyl}-3-methyl-1H-pyrazol-4-yl)oxy]benzonitrile

The amine of Preparation 21 (153 mg, 0.870 mmol) was added in oneportion to a stirred solution of the bromide of Preparation 18 (100 mg,0.271 mmol) in isopropanol (5 ml) at room temperature. The mixture washeated at 50° C. for 12 hours, cooled to room temperature andconcentrated under reduced pressure to leave a yellow oil. The oil wasdissolved in 1M aqueous sodium hydroxide solution and the resultingsolution was stirred at room temperature for 1 hour. The aqueous wasextracted with ethyl acetate (3×20 ml) and the combined organic phaseswere dried over magnesium sulphate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (20 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.14 (s, 3H), 2.71 (m, 2H), 3.50 (s, 1H),3.58 (s, 2H), 3.67 (m, 2H), 3.72 (s, 2H), 6.99 (s, 1H), 7.09 (s, 1H),7.31 (s, 1H), 7.41 (d, 2H), 7.58 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 422.

EXAMPLE 933-Chloro-5-({3-methyl-5-[(2-methyl-1H-imidazol-1-yl)methyl]-1H-pyrazol-4-yl})oxy)benzonitrile

A suspension of the bromide of Preparation 18 (100 mg, 0.264 mmol),2-methylimidazole (111 mg, 1.35 mmol) and sodium carbonate (143 mg, 1.35mmol) in toluene (5 ml) was heated at 100° C. for 12 hours. Thesuspension was cooled to room temperature, 1M aqueous sodium hydroxidesolution (5 ml) was added and the mixture was stirred for 1 hour. Themixture was extracted with ethyl acetate (3×20 ml) and the combinedorganic phases were dried over magnesium sulphate, filtered andconcentrated under reduced pressure to leave a white solid. The crudeproduct was purified by flash column chromatography on silica geleluting with dichloromethane:methanol:ammonia (95:4.5:0.5, by volume) toprovide the title compound (77 mg) as a white solid, m.p. 212-214° C.

¹H-NMR (300 MHz, CDCl₃): δ=2.14 (s, 3H), 2.33 (s, 3H), 4.92 (s, 2H),6.76 (s, 1H), 6.79 (s, 1H), 6.86 (s, 1H), 7.27 (s, 2H).

LRMS (thermospray): m/z [MH⁺] 328.

EXAMPLE 942-(4-(3,5-Dichlorophenoxy)-3-methyl-5-{[(3-pyridinylmethyl)amino]methyl}-1H-pyrazol-1-yl)ethanol

Tetrabutylammonium fluoride (0.58 ml of a 1.0M solution intetrahydrofuran, 0.580 mmol) was added in one portion to a stirredsolution of the amine of Preparation 22 (150 mg, 0.290 mmol) indichloromethane (5 ml) at room temperature. The reaction was stirred for12 hours and concentrated under reduced pressure to leave a colourlessoil. The crude product was purified by flash column chromatography onsilica gel eluting with dichloromethane:methanol:ammonia (95:4:1, byvolume) to provide the title compound (100 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=2.07 (s, 3H), 3.65 (s, 2H), 3.76 (s, 2H),3.96 (m, 2H), 4.24 (m, 2H), 6.76 (s, 2H), 7.02 (s, 1H), 7.26 (m, 1H),7.59 (d, 1H), 8.50 (m, 2H).

LRMS (thermospray): m/z [MH⁺] 407.

EXAMPLE 955-[(3-Isopropyl-5-methyl-1H-pyrazol-4-yl)oxy]isophthalonitrile

Hydrazine hydrate (110 μl, 2.24 mmol) was added to a stirred solution ofthe β-diketone of Preparation 24 (550 mg, 2.04 mmol) in glacial aceticacid (5 ml) and the resulting solution was stirred at room temperaturefor 1 hour. The mixture was concentrated under reduced pressure and theresidue was purified by flash column chromatography on silica geleluting with pentane:ethyl acetate (60:40, by volume) to provide thetitle compound (350 mg) as a yellow solid, m.p. 142-144° C.

¹H-NMR (300 MHz, CDCl₃): δ=1.21 (d, 6H), 2.09 (s, 3H), 2.90 (sept, 1H),7.40 (s, 2H), 7.60 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 267.

EXAMPLE 965-{[1-(2-Hydroxyethyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]oxy}isophthalonitrile

Tetrabutylammonium fluoride (0.28 ml of a 1.0M solution intetrahydrofuran, 0.280 mmol) was added in one portion to a stirredsolution of the pyrazole of Preparation 25 (60 mg, 0.140 mmol) indichloromethane (5 ml) at room temperature. The reaction was stirred for12 hours and concentrated under reduced pressure to leave a colourlessoil. The crude product was purified by flash column chromatography onsilica gel eluting with pentane:ethyl acetate (20:80, by volume) toprovide the title compound (30 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ=1.17 (d, 6H), 2.08 (s, 3H), 2.76 (sept, 1H),3.52 (m, 2H), 4.10 (m, 2H), 7.40 (s, 2H), 7.59 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 311.

Microanalysis: Found: C, 65.44; H, 5.87; N, 17.91. C₁₇H₁₈N₄O₂ requiresC, 65.79; H, 5.85; N, 18.05%.

EXAMPLE 973-(3,5-Dichlorophenoxy)-2-ethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Lithium diisopropylamide (18.0 ml of a 1.5M solution in cyclohexane,27.0 mmol) was added dropwise to a stirred solution of the pyrazole ofPreparation 26 (12.3 g, 24.6 mmol) in tetrahydrofuran (120 ml) at −78°C. under nitrogen. The reaction was stirred for 14 hours, slowly warmingto room temperature, and cautiously quenched with saturated aqueousammonium chloride solution (20 ml). The mixture was concentrated underreduced pressure and the residue was dissolved in dichloromethane (200ml). The resulting solution was washed with saturated aqueous ammoniumchloride solution (100 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure to leave a white solid. The solidwas triturated with a mixture of dichloromethane and pentane (100 ml and100 ml) to give the title compound (2.63 g) as a white solid, m.p.220-223° C.

¹H-NMR (400 MHz, D₆ DMSO): δ=1.08 (t, 3H), 2.44 (q, 2H), 3.60 (m, 2H),4.24 (t, 2H), 7.00 (s, 2H), 7.26 (s, 1H), 8.15 (s, 1H).

LRMS (thermospray): m/z [MNH₄ ⁺] 343.

Microanalysis: Found: C, 51.52; H, 3.98; N, 12.74. C₁₄H₃₁Cl₂N₃O₂requires C, 51.55; H, 4.02; N, 12.88%.

EXAMPLE 983-(3,5-Dichlorophenoxy)-2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

Borane (2.00 ml of a 1.0M solution in tetrahydrofuran, 2.00 mmol) wasadded to a stirred solution of the pyrazole of Example 97 (326 mg, 1.00mmol) in tetrahydrofuran (10 ml) at room temperature under nitrogen. Thereaction was heated under reflux for 5 hours and further borane (3.00 mlof a 1.0M solution in tetrahydrofuran, 3.00 mmol) was added. Thereaction was heated under reflux for 14 hours and further borane (2.00ml of a 1.0M solution in tetrahydrofuran, 2.00 mmol) was added. Thereaction was heated under reflux for 3 hours and further borane (2.00 mlof a 1.0M solution in tetrahydrofuran, 2.00 mmol) was added. The mixturewas cooled to room temperature, 2M hydrochloric acid (10 ml) was addedand the mixture was heated under reflux for 1 hour, The mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (40 ml), washed with 1M aqueouspotassium carbonate solution (30 ml), dried over magnesium sulphate,filtered and concentrated under reduced pressure. The crude product waspurified by flash column chromatography on silica gel eluting withdichloromethane:methanol (98:2, by volume), thendichloromethane:methanol (95:5, by volume) and thendichloromethane:methanol:ammonia (90:9:1, by volume) to provide thetitle compound (219 mg) as a white solid, m.p. 76-77° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (t, 3H), 2.42 (q, 2H), 3.24 (t, 2H),3.80 (s, 2H), 4.05 (t, 2H), 6.76 (s, 2H), 6.95 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 312.

Microanalysis: Found: C, 53.79; H, 4.88; N, 13.14. C₁₄H₁₅Cl₂N₃O requiresC, 53.86; H. 4.84; N, 13.46%.

EXAMPLE 993-(3,5-Dichlorophenoxy)-2-ethyl-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

Methyl iodide (11 μl, 0.176 mmol) was added to a stirred solution ofpotassium carbonate (24 mg, 0.176 mmol) and the amine of Example 98 (50mg, 0.160 mmol) in N,N-dimethylformamide (2 ml) at room temperatureunder nitrogen. The reaction was stirred for 3 hours and thenconcentrated under reduced pressure. The residue was dissolved in ethylacetate (20 ml), washed with 1M aqueous potassium carbonate solution (20ml), dried over magnesium sulphate, filtered and concentrated underreduced pressure. The crude product was purified by flash columnchromatography on silica gel eluting with dichloromethane:methanol(98:2, by volume) to provide the title compound (18 mg) as a colourlessoil.

¹H-NMR (400 MHz, CDCl₃): δ=1.11 (t, 3H), 2.42 (m, 5H), 2.84 (t, 2H),3.37 (s, 2H), 4.11 (t, 2H), 6.77 (s, 2H), 6.98 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 326.

EXAMPLE 1004-[(3-(3,5-Dichlorophenoxy)-2-ethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl]benzonitrile

4-Cyanobenzylbromide (35 mg, 0.176 mmol) was added to a stirred solutionof potassium carbonate (24 mg, 0.176 mmol) and the amine of Example 98(50 mg, 0.160 mmol) in N,N-dimethylformamide (2 ml) at room temperatureunder nitrogen. The reaction was stirred for 14 hours and thenconcentrated under reduced pressure. The residue was dissolved in ethylacetate (20 ml) and the resulting solution was washed with 1M aqueouspotassium carbonate solution (15 ml), dried over magnesium sulphate,filtered and concentrated under reduced pressure. The crude product waspurified by flash column chromatography on silica gel eluting withdichloromethane:methanol (98:2, by volume) to provide the title compound(66 mg) as a white solid, m.p. 149-150° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.13 (t, 3H), 2.44 (q, 2H), 2.92 (t, 2H),3.42 (s, 2H), 3.71 (s, 2H), 4.13 (t, 2H), 6.74 (s, 2H), 6.97 (s, 1H),7.42 (d, 2H), 7.60 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 427.

EXAMPLE 1013-(3,5-Dichlorophenoxy)-2-ethyl-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

4-Methoxybenzylchloride (24 μl, 0.176 mmol) was added to a stirredsolution of potassium carbonate (24 mg, 0.176 mmol) and the amine ofExample 98 (50 mg, 0.160 mmol) in N,N-dimethylformamide (6 ml) at roomtemperature under nitrogen. The reaction was stirred for 14 hours andthen potassium carbonate (12 mg, 0.088 mmol) and 4-methoxybenzylchloride(12 μl, 0.088 mmol) added. The reaction was stirred for 3 hours and thenconcentrated under reduced pressure. The residue was dissolved in ethylacetate (20 ml) and the resulting solution was washed with 1M aqueouspotassium carbonate solution (20 ml), dried over magnesium sulphate,filtered and concentrated under reduced pressure. The crude product waspurified by flash column chromatography on silica gel eluting withdichloromethane:methanol (99:1, by volume) to provide the title compound(50 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.13 (t, 3H), 2.45 (q, 2H), 2.92 (t, 2H),3.44 (s, 2H), 3.60 (s, 2H), 3.80 (s, 3H), 4.10 (t, 2H), 6.77 (s, 2H),6.85 (d, 2H), 7.00 (s, 1H), 7.23 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 432.

EXAMPLE 102[1-(2-Aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-5-yl]methanol

Hydrogen chloride (0.50 ml of a 4.0M solution in dioxane, 2.00 mmol) wasadded to a stirred solution of the pyrazole of Example 135 (86 mg, 0.200mmol) in dioxane (0.5 ml) at room temperature under nitrogen. Thereaction was stirred for 24 hours and concentrated under reducedpressure. The residue was dissolved in dichloromethane (20 ml) and theresulting solution was washed with 1M aqueous potassium carbonatesolution (10 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel eluting with dichloromethane:methanol(99:1, by volume) to provide the title compound (40 mg) as a whitesolid, m.p. 105-107° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (t, 3H), 2.42 (q, 2H), 2.55 (s, 2H),3.13 (t, 2H), 4.13 (t, 2H), 4.37 (s, 2H), 6.79 (s, 2H), 6.98 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 330.

Microanalysis: Found: C, 50.61; H, 5.23; N, 12.31. C₁₄H₁₇Cl₂N₃O₂requires C, 50.92; H, 5.19; N, 12.73%.

EXAMPLE 1032-[4-(3,5-Dichlorophenoxy)-5-(ethoxymethyl)-3-ethyl-1H-pyrazol-1-yl]ethylamine

Hydrogen chloride (0.50 ml of a 4.0M solution in dioxane, 2.00 mmol) wasadded to a stirred solution of the pyrazole of Example 136 (60 mg, 0.130mmol) in dioxane (0.5 ml) at room temperature under nitrogen. Thereaction was stirred for 2 days and concentrated under reduced pressure.The residue was dissolved in dichloromethane (20 ml) and the resultingsolution was washed with 1M aqueous potassium carbonate solution (10ml), dried over magnesium sulphate, filtered and concentrated underreduced pressure. The crude product was purified by flash chromatographyon silica gel eluting with dichloromethane:methanol:ammonia (99:9:1, byvolume) to provide the title compound (32 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.42 (q, 2H), 3.15 (t, 2H),3.40 (q, 2H), 4.11 (t, 2H), 4.29 (s, 2H), 6.79 (s, 2H), 6.98 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 358.

EXAMPLES 104 TO 106

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 103 using theappropriate starting material.

Example No. LRMS (Starting material) R (thermospray) Analytical Data 104(Example 140)

m/z [MH⁺] 380. ¹H-NMR (400 MHz, CDCl₃): δ = 1.10 (t, 3 H), 2.40 (q, 2H), 2.97 (t, 2 H), 4.15 (t, 2 H), 5.20 (s, 2 H), 6.16 (s, 1 H), 6.71 (d,2 H), 6.97 (s, 1 H), 7.15 (s, 1 H), 7.42 (s, 1 H). Microanalysis: Found:C, 52.78; H, 5.09; N, 17.86. C₁₇H₁₉Cl₂N₅O. 0.12 CH₂Cl₂ requires C,52.66; H, 4.97; N, 17.94%. 105 (Example 142)

m/z [MH⁺] 449. ¹H-NMR (400 MHz, CDCl₃): δ = 1.10 (t, 3 H), 2.42 (q, 2H), 3.11 (t, 2 H), 3.55 (s, 2 H), 3.60 (s, 2 H), 3.75 (s, 3 H), 4.07 (t,2 H), 6.73 (s, 2 H), 6.79 (d, 2 H), 6.97 (s, 1 H), 7.10 (d, 2 H).Microanalysis: Found: C, 56.88; H, 5.67; N, 11.88. C₂₂H₂₆Cl₂N₄O₂. 0.23CH₂Cl₂ requires C,56.94; H, 5.69; N, 11.95%. 106 (Example 143)

m/z [MH⁺] 444. ¹H-NMR (400 MHz, CDCl₃): δ = 1.10 (t, 3 H), 2.41 (q, 2H), 3.15 (t, 2 H), 3.60 (s, 2 H), 3.74 (s, 2 H), 4.10 (d, 2 H), 6.73 (s,2 H), 6.97 (s, 1 H), 7.29 (d, 2 H), 7.53 (d, 2 H). Microanalysis: Found:C, 57.53; H, 5.09; N, 15.05. C₂₂H₂₃Cl₂N₅O. 0.22 CH₂Cl₂ requires C,57.64; H, 5.10; N, 15.12%.

EXAMPLE 1072-[5-[(4-Acetyl-1-piperazinyl)methyl]-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl]ethylamine

Trifluoroacetic acid (1 ml) was added to a stirred solution of thepyrazole of Example 139 (150 mg, 0.28 mmol) in dichloromethane (2 ml) atroom temperature under nitrogen. The reaction was stirred for 3 hoursand the mixture was concentrated under reduced pressure. The residue wasdissolved in dichloromethane (20 ml) and the resulting solution waswashed with 1M aqueous potassium carbonate solution (30 ml), dried overmagnesium sulphate, filtered and concentrated under reduced pressure.The crude product was purified by flash chromatography on silica geleluting with dichloromethane:methanol:ammonia (90:9:1, by volume) toprovide the title compound (103 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.11 (t, 3H), 2.05 (s, 3H), 2.32 (m, 4H),2.42 (q, 2H), 3.13 (m, 2H), 3.33 (s, 2H), 3.34 (m, 2H), 3.52 (m, 2H),4.15 (t, 2H), 6.73 (s, 2H), 6.97 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 440.

EXAMPLE 108N-[2-({[1-(2-Aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-5-yl]methyl}-amino)ethyl]acetamide

Trifluoroacetic acid (1 ml) was added to a stirred solution of thepyrazole of Example 141 (122 mg, 0.24 mmol) in dichloromethane (2 ml) atroom temperature under nitrogen. The reaction was stirred for 3 hoursand the mixture was concentrated under reduced pressure. The residue wasdissolved in dichloromethane (50 ml) and the resulting solution waswashed with 1M aqueous potassium carbonate solution (30 ml), dried overmagnesium sulphate, filtered and concentrated under reduced pressure.The crude product was purified by flash chromatography on silica geleluting with dichloromethane:methanol:ammonia (90:9:1, by volume) toprovide the title compound (64 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.15 (t, 3H), 1.95 (s, 3H), 2.45 (q, 2H),2.69 (t, 2H), 3.20 (t, 2H), 3.27 (m, 2H), 3.65 (s, 2H), 4.15 (t, 2H),6.31 (s, 1H), 6.81 (s, 2H), 7.02 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 414.

EXAMPLE 109[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]methanaminehydrobromide

The bromide of Preparation 8 (500 mg, 1.30 mmol) was added portionwiseto a saturated solution of ammonia in isopropanol (50 ml) at 0° C. Thereaction was stirred for 2 hours and allowed to slowly warm to roomtemperature. The mixture was concentrated under reduced pressure and theresulting solid was triturated with diethyl ether to provide the titlecompound (340 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ=2.38 (s, 3H), 4.78 (s, 2H), 6.88 (s, 2H),7.19 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 272.

EXAMPLE 110N-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}-N-(4-fluorobenzyl)amine

Sodium triacetoxyborohydride (36 mg, 0.160 mmol) was added in oneportion to a stirred solution of the pyrazole of Example 109 (150 mg,0.400 mmol), 4-fluorobenzaldehyde (11 mg, 0.080 mmol) and acetic acid (3drops) in dichloromethane (15 ml) at room temperature under nitrogen.The reaction was stirred for 3 hours and then concentrated under reducedpressure. The crude product was purified by flash chromatography onsilica gel eluting with dichloromethane:methanol:ammonia (90:9:1, byvolume) to provide the title compound (6 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.17 (s, 3H), 3.67 (s, 2H), 3.73 (s, 2H),6.81 (s, 2H), 6.99 (s, 2H), 7.02 (s, 1H), 7.22 (s, 2H).

LRMS (electrospray): m/z [M-H⁺] 378.

EXAMPLE 1114-[({[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}amino)methyl]benzonitrile

Sodium triacetoxyborohydride (216 mg, 1.09 mmol) was added in oneportion to a stirred solution of the pyrazole of Example 109 (300 mg,0.850 mmol), 4-cyanobenzaldehyde (111 mg, 0.850 mmol) and acetic acid (3drops) in dichloromethane (25 ml) at room temperature tinder nitrogen.The reaction was stirred for 14 hours and then washed with 1M aqueoussodium carbonate solution (2×10 ml) and brine (10 ml), dried overmagnesium sulphate, filtered and concentrated under reduced pressure.The crude product was purified by flash chromatography on silica geleluting with dichloromethane:methanol:ammonia (95:4:1, by volume) toprovide the title compound (10 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.16 (s, 3H), 3.70 (s, 2H), 3.85 (s, 2H),6.78 (s, 2H), 7.01 (s, 2H), 7.35 (d, 2H), 7.58 (d, 2H).

LRMS (electrospray): m/z [MH⁺] 387.

EXAMPLE 1123-Chloro-5-[(1,3,5-trimethyl-1H-pyrazol-4-yl)oxy]benzonitrile

Methyl hydrazine (250 mg, 5.17 mol) was added to a stirred solution ofthe β-diketone of Preparation 16 (1.00 g, 3.97 mmol) in glacial aceticacid (10 ml) and the resulting solution was stirred at room temperaturefor 2 days. The mixture was concentrated under reduced pressure and theresulting orange oil was purified by flash column chromatography onsilica gel eluting with pentane:ethyl acetate (50:50, by volume) toprovide the title compound (500 mg) as a white solid, m.p. 114-116° C.

¹H-NMR (300 MHz, CDCl₃): δ=1.85 (s, 3H), 1.87 (s, 3H), 3.61 (s, 3H),6.88 (s, 1H), 6.98 (s, 1H), 7.11 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 262.

Microanalysis: Found: C, 59.48; H, 4.60; N, 15.88. C₁₃H₁₂N₃OCl requiresC, 59.66; H, 4.62; N, 16.06%.

EXAMPLE 1133-Chloro-5-[(5-{[(4-cyanobenzyl)amino]methyl}-1,3-dimethyl-1H-pyrazol-4-yl)oxy]benzonitrile

4-Cyanobenzylamine (155 mg, 1.17 mmol) was added in one portion to astirred solution of the bromide of Example 144 (100 mg, 0.300 mmol) inisopropanol (10 ml) at room temperature. The mixture was heated at 50°C. for 1 hour, cooled to room temperature and concentrated under reducedpressure to leave a yellow oil. The crude product was purified by flashcolumn chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (97 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.03 (s, 3H), 3.66 (s, 2H), 3.79 (s, 2H),3.84 (s, 3H), 7.02 (s, 1H), 7.13 (s, 1H), 7.31 (s, 1H), 7.37 (d, 2H),7.58 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 392.

EXAMPLE 1143-Chloro-5-{[1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl]oxy}benzonitrile

2-Hydroxyethyl hydrazine (1.80 g, 24.0 mol) was added to a stirredsolution of the β-diketone of Preparation 16 (5.80 g, 23.0 mmol) inglacial acetic acid (30 ml) and the resulting solution was stirred atroom temperature for 2 days. The mixture was concentrated under reducedpressure and the resulting brown oil was purified by flash columnchromatography on silica gel eluting with pentane:ethyl acetate (50:50,by volume) to provide the title compound (4.80 g) as a yellow solid,m.p. 114-116° C.

¹H-NMR (300 MHz, CDCl₃): δ=2.04 (s, 3H), 2.12 (s, 3H), 3.24 (s, 1H),4.08 (m, 4H), 7.03 (s, 1H), 7.15 (s, 1H), 7.28 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 292.

Microanalysis: Found: C, 57.40; H. 4.86; N, 14.14. C₁₄H₁₄N₃O₂Cl requiresC, 57.69; H, 4.84; N, 14.40%.

EXAMPLE 1153-Chloro-5-{[5-{[(4-cyanobenzyl)amino]methyl}-1-(2-hydroxyethyl)-3-methyl-1H-pyrazol-4-yl]oxy}benzonitrile

4-Cyanobenzylamine (131 mg, 0.910 mmol) was added to a stirred solutionof the pyrazole of Preparation 30 (120 mg, 0.240 mmol) inN-methylpyrrolidine (10 ml) and the resulting solution was heated at 60°C. for 3 hours. The mixture was concentrated under reduced pressure andthe resulting brown oil was dissolved in acetic acid (10 ml) and heatedat 40° C. for 6 hours. The mixture was concentrated under reducedpressure and the crude product was purified by flash columnchromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (5 mg) as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ=2.05 (s, 3H), 3.04 (s, 2H), 3.91 (s, 2H),3.99 (t, 2H), 4.32 (m, 2H), 7.06 (s, 1H), 7.11 (s, 1H), 7.33 (s, 1H),7.46 (d, 2H), 7.62 (d, 2H).

LRMS (thermospray): m/z [MNa⁺] 444.

EXAMPLE 1164-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}amino)methyl]benzamide

The amine of Preparation 55 (150 mg, 0.800 mmol) was added to a stirredsolution of the pyrazole of Preparation 18 (100 mg, 0.270 mmol) andtriethylamine (81 mg, 0.800 mmol) in isopropanol (10 ml) andN,N-dimethylformamide (5 ml) and the resulting solution was heated at60° C. for 3 hours. The mixture was concentrated under reduced pressureand the resulting brown oil was dissolved in ethyl acetate (20 ml). Thesolution was washed with 1M aqueous sodium carbonate solution (2×10 ml)and brine (10 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel eluting withdichloromethane:methanol:ammonia (90:9:1, by volume) to provide thetitle compound (5 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=2.16 (s, 3H), 3.68 (s, 2H), 3.82 (s, 2H),7.05 (s, 1H), 7.13 (s, 1H), 7.28 (s, 1H), 7.32 (d, 2H), 7.76 (d, 2H).

LRMS (electrospray): m/z [MH⁺] 396.

EXAMPLES 117 TO 120

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 114 using theappropriate diketone starting material and 2-hydroxyethylhydrazine.

Example No. (Diketone No.) R LRMS Analytical Data 117 F m/z [MH⁺] 303.¹H-NMR (300 MHz, CDCl₃): δ = 1.10 (m, 6H), 2.39 (q, 2H), 2.49 (q,(Preparation 43) (thermospray) 2H), 4.04 (m, 4H), 6.85 (dd, 1H), 6.99(s, 1H), 7.00 (dd, 1H). Microanalysis: Found: C, 62.96; H, 5.94; N,13.75. C₁₆H₁₈N₃O₂F requires C, 63.35; H, 5.98; N, 13.85%. 118 Me m/z[MH⁺] 300. ¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (t, 3H), 1.12 (t, 3H), 2.34(s, 3H), (Preparation 44) (electrospray) 2.39 (q, 2H), 2.50 (q, 2H),3.70 (s, 1H), 4.60 (m, 4H), 6.91 (s, 1H), 6.97 (s, 1H), 7.10 (s, 1H).119 CN m/z [MH⁺] 311. ¹H-NMR (400 MHz, CDCl₃): δ = 1.13 (m, 6H), 2.40(q, 2H), 2.53 (q, (Preparation 45) (electrospray) 2H), 3.53 (m, 1H),4.11 (m, 4H), 7.40 (s, 2H), 7.58 (s, 1H). Microanalysis: Found: C,65.64; H, 5.84; N, 18.05. C₁₇H₁₈N₄O₂ requires C, 65.79; H, 5.85; N,18.05%. m.p. 120-121° C. 120 Cl m/z [MH⁺] 320. ¹H-NMR (400 MHz, CDCl₃):δ = 1.08 (m, 6H), 2.39 (q, 2H), 2.50 (q, (Preparation 46) (thermospray)2H), 4.01 (m, 2H), 4.08 (m, 2H), 7.03 (s, 1H), 7.13 (s, 1H), 7.24 (s,1H). Microanalysis: Found: C, 59.67; H, 5.71; N, 12.99. C₁₆H₁₈N₃O₂Clrequires C, 60.09; H, 5.67; N, 13.14%.

EXAMPLES 121 TO 124

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 76 using theappropriate diketone starting material and hydrazine.

Example No. (Diketone No.) R LRMS Analytical Data 121 F m/z [MH⁺] 260.¹H-NMR (400 MHz, CDCl₃): δ = 1.18 (t, 6H), 2.47 (q, 4H), 6.85 (dd,(Preparation 43) (thermospray) 1H), 6.98 (s, 1H), 7.01 (dd, 1H). 122 CNm/z [MH⁺] 267. ¹H-NMR (400 MHz, CDCl₃): δ = 1.20 (6H, m), 2.47 (q, 4H),7.39 (s, (Preparation 45) (thermospray) 2H), 7.59 (s, 1H). 123 Me m/z[MH⁺] 256. ¹H-NMR (400 MHz, CDCl₃): δ = 1.17 (t, 6H), 2.34 (s, 3H), 2.48(q, 4H), (Preparation 44) (electrospray) 6.92 (s, 1H), 6.96 (s, 1H),7.10 (s, 1H). 124 Cl m/z [MH⁺] 276. ¹H-NMR (400 MHz, CDCl₃): δ = 1.18(t, 6H), 2.49 (q, 4H), 7.07 (s, 1H), (Preparation 46) (thermospray) 7.13(s, 1H), 7.27 (s, 1H).

EXAMPLES 125 TO 128

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 13 using theappropriate pyrazole starting material and chloroethylaminehydrochloride.

Example No. (Starting pyrazole No.) R LRMS Analytical Data 125 Me m/z[MH⁺] 299. ¹H-NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6H), 2.34 (s, 3H), 2.39(q, (Example 123) (electrospray) 2H), 2.43 (q, 2H), 3.17 (t, 2H), 4.04(t, 2H), 6.91 (s, 1H), 6.96 (s, 1H), 7.09 (s, 1H). 126 Cl m/z [MH⁺] 319.¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (m, 6H), 2.40 (q, 2H), 2.51 (q,(Example 124) (thermospray) 2H), 3.15 (m, 2H), 4.02 (m, 2H), 7.04 (s,1H), 7.12 (s, 1H), 7.28 (s, 1H). 127 CN m/z [MH⁺] 310. ¹H-NMR (400 MHz,CDCl₃): δ = 1.09 (m, 6H), 2.38 (q, 2H), 2.50 (q, (Example 122)(thermospray) 2H), 3.15 (m, 2H), 4.03 (m, 2H), 7.39 (s, 2H), 7.57 (s,1H). 128 F m/z [MH⁺] 303. ¹H-NMR (400 MHz, CDCl₃): δ = 1.06 (m, 6H),2.37 (q, 2H), 2.48 (q, (Example 121) (thermospray) 2H), 3.13 (t, 2H),4.03 (t, 2H), 6.84 (d, 1H), 6.94 (s, 1H), 6.97 (d, 1H).

EXAMPLES 129 TO 131

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 76 using theappropriate diketone starting material and hydrazine.

Example No. (Diketone No.) R R′ LRMS Analytical Data 129 cycloPr Et m/z[MH⁺] 279. ¹H-NMR (400 MHz, CDCl₃): 0.73 (m, 2H), 0.81 (m, 2H), 1.16 (t,3H), (Preparation 52) (electrospray) 1.58 (m, 1H), 2.46 (q, 2H), 7.42(s, 2H), 7.58 (s, 1H). m.p. 136-141° C. 130 tBu Me m/z [MH⁺] 281. ¹H-NMR(300 MHz, CDCl₃): 1.21 (s, 9H), 1.94 (s, 3H), 7.34 (s, 2H), (Preparation53) (electrospray) 7.56 (s, 1H). Microanalysis: Found: C, 68.18; H,5.74; N, 19.72. C₁₆H₁₆N₄O requires C, 68.55; H, 5.75; N, 19.99%. m.p.61-63° C. 131 iPr Et m/z [MH⁺] 281. ¹H-NMR (400 MHz, CDCl₃): 1.15 (m,9H), 2.41 (q, 2H), 2.82 (m, 1H), (Preparation 54) (electrospray) 7.36(s, 2H), 7.58 (s, 1H). m.p. 136-141° C.

EXAMPLE 1324-(3,5-Dichlorophenoxy)-3,5-diethyl-1-(1-methyl-3-azetidinyl)-1H-pyrazole

Paraformaldehyde (30 mg, 0.330 mmol) was added in one portion to astirred solution of the pyrazole of Example 51 (120 mg, 0.330 mmol) informic acid (2 ml) at room temperature. The mixture was heated at 100°C. for 5 hours, cooled to room temperature and concentrated underreduced pressure to leave a colourless oil. The oil was dissolved inethyl acetate (50 ml) and the resulting solution was washed withsaturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) andbrine (20 ml), dried over magnesium sulphate, filtered and concentratedunder reduced pressure. The crude product was purified by flash columnchromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (85 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=1.08 (t, 3H), 1.16 (t, 3H), 2.49 (m, 7H),3.63 (m, 2H), 3.81 (m, 2H), 4.79 (m, 1H), 6.79 (s, 2H), 7.00 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 354.

EXAMPLES 133-134 2-[4-(3,5-Dichlorophenoxy)-3-ethyl-1f+pyrazol-1-yl]ethylamine (Example 133) and2-[4-(3,5-Dichlorophenoxy)-5-ethyl-1H-pyrazol-1-yl]ethylamine (Example134)

A mixture of the pyrazole (1.03 g, 4.00 mmol) of Example 42 andchloroethylamine hydrochloride (510 mg, 4.40 mmol) was stirred andheated at 150° C. for 24 hours. After cooling the mixture waspartitioned between 1M aqueous potassium carbonate solution (30 ml) anddichloromethane (30 ml). The organic layer was washed with brine (30ml), dried over magnesium sulphate, filtered and concentrated underreduced pressure. The resulting brown oil was purified by flashchromatography on silica gel eluting withdichloromethane:methanol:ammonia (93:6:1, by volume) to afford the titlecompounds (768 mg) in a 85:15 ratio of regioisomers as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.16 (major, t, 3H), 1.16 (minor, t, 3H),2.48 (major, q, 2H), 2.60 (minor, q, 2H), 3.13 (major, t, 2H), 3.19(minor, t, 2H), 4.10 (major, t, 2H), 4.10 (minor, t, 2H), 6.85 (major,s, 2H), 6.85 (minor, s, 2H), 7.02 (major, s, 1H), 7.02 (minor, s, 1H),7.27 (major, s, 1H), 7.31 (minor, s, 1H).

LRMS (thermospray): m/z [MH⁺] 300.

EXAMPLE 135 tert-Butyl2-[4-(3,5-dichlorophenoxy)-3-ethyl-5-(hydroxymethyl)-1H-pyrazol-1-yl]ethylcarbamate

A solution of the pyrazole of Example 97 (1.96, 6.00 mmol) inconcentrated hydrochloric acid (50 ml) was heated under reflux for 20hours. The reaction was cooled to room temperature and concentratedunder reduced pressure. The residue was dissolved in dioxane (80 ml) andwater (60 ml), di-t-butyldicarbonate (1.44 g, 6.60 mmol) and sodiumhydrogencarbonate (1.26 g, 15.0 mmol) were added and the reaction wasstirred at room temperature for 3 days. The reaction was concentratedunder reduced pressure. A solution of the residue in dichloromethane(300 ml) was washed with 2M aqueous hydrochloric acid (100 ml), driedover magnesium sulphate, filtered and concentrated under reducedpressure. A solution of the crude product in tetrahydrofuran (50 ml) wascooled to −40° C. under nitrogen and triethylamine (0.79 ml, 5.68 mmol)and isopropylchloroformate (5.68 ml of a 1.0M solution in toluene, 5.68mmol) were added dropwise. The reaction was stirred at −40° C. for 40minutes and then warmed to 0° C. Sodium borohydride (537 mg, 14.2 mmol)was added in one portion and then water (3 drops) was added and thereaction was stirred at 0° C. for 1 hour and at room temperature for 14hours. The mixture was concentrated under reduced pressure and asolution of the residue in dichloromethane (100 ml) was washed withwater (100 ml), dried over magnesium sulphate, filtered and concentratedunder reduced pressure. The crude product was purified by flashchromatography on silica gel eluting with dichloromethane:methanol(97:3, by volume) to provide the title compound (1.37 g) as a whitefoam.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (t, 3H), 1.37 (s, 9H), 2.40 (q, 2H),3.00 (s, 1H), 3.56 (m, 2H), 4.20 (t, 2H), 4.48 (d, 2H), 5.00 (m, 1H),6.80 (s, 2H), 6.97 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 430.

EXAMPLE 136 tert-Butyl2-[4-(3,5-dichlorophenoxy)-5-(ethoxymethyl)-3-ethyl-1H-pyrazol-1-yl]ethylcarbamate

Silver(I) oxide (210 mg, 0.900 mmol) was added in one portion to astirred solution of the alcohol of Example 135 (129 mg, 0.300 mmol) inethyl iodide (1.75 ml) at room temperature under nitrogen. The reactionwas heated at 40° C. for 1 day and then cooled to room temperature. Themixture was filtered and the residual solid was washed withdichloromethane (10 ml). The filtrate was concentrated under reducedpressure. The crude product was purified by flash chromatography onsilica gel eluting with dichloromethane:methanol (99:1, by volume) toprovide the title compound (60 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.15 (m, 6H), 1.44 (s, 9H), 2.45 (q, 2H),3.45 (q, 2H), 3.58 (m, 2H), 4.18 (m, 2H), 4.29 (s, 2H), 5.26 (m, 1H),6.92 (s, 2H), 7.00 (s, 1H).

LRMS (electrospray): m/z [MNa⁺] 480.

EXAMPLE 137 tert-Butyl2-[5-(bromomethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl]ethylcarbamate

Bromine (160 μl, 3.12 mmol) was added dropwise to a stirred solution oftriphenylphosphine (820 mg, 3.12 mmol) and imidazole (213 mg, 3.12 mmol)in dichloromethane (15 ml) at room temperature under nitrogen. Asolution of the alcohol of Example 135 (1.12 g, 2.60 mmol) indichloromethane (5 ml) was then added to the reaction. The reaction wasstirred at room temperature for 2 hours, diluted with dichloromethane(50 ml), washed with brine (20 ml), dried over magnesium sulphate,filtered and concentrated under reduced pressure. The crude product waspurified by flash chromatography on silica gel eluting withdichloromethane:methanol (98:2, by volume) to provide the title compound(969 mg) as a white foam.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (t, 3H), 1.40 (s, 9H), 2.40 (q, 2H),3.60 (m, 2H), 4.18 (t, 2H), 4.27 (s, 2H), 4.95 (s, 1H), 6.82 (s, 2H),7.00 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 494.

Microanalysis: Found: C, 46.22; H, 4.89; N, 8.44. C₁₉H₂₄BrCl₂N₃O₃requires C, 46.27; H, 4.90; N,

8.52%.

EXAMPLE 138 tert-Butyl2-[5-(aminomethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl]ethylcarbamate

The bromide of Example 137 (444 mg, 0.900 mmol) was added to a saturatedsolution of ammonia in isopropanol (25 ml) and diisopropylethylamine(173 μl, 1.00 mmol) at room temperature. The reaction was stirred for 5hours and then concentrated under reduced pressure. The crude productwas purified by flash chromatography on silica gel eluting withdichloromethane:methanol (95:5, by volume) to provide the title compound(359 mg) as a white solid, m.p. 112-114° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.11 (t, 3H), 1.40 (s, 9H), 2.40 (q, 2H),3.55 (m, 2H), 3.73 (s, 2H), 4.18 (t, 2H), 5.60 (s, 1H), 6.77 (s, 2H),6.98 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 429.

EXAMPLE 139 tert-Butyl2-[5-[(4-acetyl-1-piperazinyl)methyl]-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl]ethylcarbamate

N-Acetylpiperazine (42 mg, 0.330 mmol) in N,N-dimethylformamide (1 ml)was added to a stirred solution of the bromide of Example 137 (148 mg,0.300 mmol) and diisopropylethylamine (57 μL, 0.330 mmol) inN,N-dimethylformamide (2 ml) at room temperature. The reaction wasstirred for 5 hours and the mixture was concentrated under reducedpressure. A solution of the residue in dichloromethane (30 ml) waswashed with 1M aqueous potassium carbonate solution (10 ml), dried overmagnesium sulphate, filtered and concentrated under reduced pressure.The crude product was purified by flash chromatography on silica geleluting with dichloromethane:methanol (98:2, by volume) to provide thetitle compound (150 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.15 (t, 3H), 1.42 (s, 9H), 2.06 (s, 3H),2.44 (m, 6H), 3.32 (s, 2H), 3.47 (m, 2H), 3.60 (m, 2H), 3.65 (m, 2H),4.23 (m, 2H), 5.89 (s, 1H), 6.76 (s, 2H), 7.02 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 540.

EXAMPLE 140 tert-Butyl2-[4-(3,5-dichlorophenoxy)-3-ethyl-5-(1H-pyrazol-1-ylmethyl)-1H-pyrazol-1-yl]ethylcarbamate

Pyrazole (23 mg, 0.330 mmol) was added in one portion to a stirredsolution of the bromide of Example 137 (148 mg, 0.300 mmol) and sodiumhydride (60% dispersion in oil, 13.2 mg, 0.330 mmol) inN,N-dimethylformamide (2 ml) at room temperature under nitrogen. Thereaction was stirred for 5 hours, quenched with water (1.00 ml) andconcentrated under reduced pressure. The residue was dissolved indichloromethane (30 ml) and the resulting solution was washed with 1Maqueous potassium carbonate solution (10 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography on silica gel eluting withdichloromethane:methanol (98:2, by volume) to provide the title compound(125 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.13 (t, 3H), 1.44 (s, 9H), 2.42 (q, 2H),3.52 (m, 2H), 4.26 (t, 2H), 5.18 (s, 2H), 5.48 (s, 1H), 6.16 (s, 1H),6.73 (s, 2H), 7.00 (s, 1H), 7.18 (s, 1H), 7.45 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 480.

EXAMPLE 141 tert-Butyl2-[5-({[2-(acetylamino)ethyl]amino}methyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl]ethylcarbamate

N-Acetylethylenediamine (153 mg, 1.50 mmol) in isopropanol (1 ml) wasadded to a stirred solution of the bromide of Example 137 (148 mg, 0.300mmol) and diisopropylethylamine (57 μl, 0.330 mmol) in isopropanol (2ml) at room temperature. The reaction was stirred for 5 hours and themixture was concentrated under reduced pressure. A solution of theresidue in dichloromethane (50 ml) was washed with 1M aqueous potassiumcarbonate solution (20 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel eluting with dichloromethane:methanol(90:10, by volume) then dichloromethane:methanol:ammonia (90:9:1, byvolume) to provide the title compound (122 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.13 (t, 3H), 1.42 (s, 9H), 1.94 (d, 3H),2.44 (q, 2H), 2.74 (m, 2H), 3.35 (m, 2H), 3.58 (m, 4H), 4.19 (m, 2H),5.68 (s, 1H), 6.77 (s, 2H), 7.00 (s, 1H), 7.65 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 514.

EXAMPLE 142 tert-Butyl2-(4-(3,5-dichlorophenoxy)-3-ethyl-5-{[(4-methoxybenzyl)amino]methyl}-1H-pyrazol-1-yl)ethylcarbamate

4-Methoxybenzaldehyde (46 μl, 0.380 mmol), the amine of Example 138 (172mg, 0.400 mmol) and magnesium sulphate (200 mg) were stirred indichloromethane (4 ml) at room temperature for 4 days. The mixture wasfiltered and the filtrate was concentrated under reduced pressure toleave a yellow oil. The oil was dissolved in methanol (4 ml) and sodiumborohydride (18 mg, 0.480 mmol) was added with vigorous stirring. Oncethe addition was complete the reaction was stirred for 4 hours and thenwater (2 ml) was added. The mixture was concentrated under reducedpressure and the residue was dissolved in dichloromethane (50 ml). Theresulting solution was washed with 1M aqueous potassium carbonatesolution (20 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel eluting with dichloromethane:methanol(99:1, by volume) and then dichloromethane:methanol (95:5, by volume) toprovide the title compound (142 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (t, 3H), 1.40 (s, 9H), 2.42 (m, 2H),3.55 (m, 5H), 3.66 (s, 2H), 3.77 (s, 2H), 4.15 (m, 2H), 6.11 (s, 1H),6.74 (s, 2H), 6.80 (d, 2H), 7.00 (s, 1H), 7.11 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 549.

EXAMPLE 143 tert-Butyl2-[5-{[(4-cyanobenzyl)amino]methyl}-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl]ethylcarbamate

A mixture of 4-cyanobenzaldehyde (50 mg, 0.380 mmol), the amine ofExample 138 (172 mg, 0.400 mmol), magnesium sulphate (200 mg) anddichloromethane (4 ml) was stirred at room temperature for 4 days. Themixture was filtered and the filtrate was concentrated under reducedpressure to leave a yellow oil. The oil was dissolved in methanol (4 ml)and sodium borohydride (18 mg, 0.480 mmol) was added with vigorousstirring. Once the addition was complete the reaction was stirred for 4hours and then water (2 ml) was added. The mixture was concentratedunder reduced pressure and the residue was dissolved in dichloromethane(50 ml). The resulting solution was washed with 1M aqueous potassiumcarbonate solution (20 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel eluting with dichloromethane:methanol(99:1, by volume) then dichloromethane:methanol (95:5, by volume) toprovide the title compound (120 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.10 (t, 3H), 1.35 (s, 9H), 2.40 (q, 2H),3.55 (m, 2H), 3.58 (s, 2H), 3.76 (s, 2H), 4.16 (m, 2H), 5.45 (s, 1H),6.73 (s, 2H), 6.98 (s, 1H), 7.32 (d, 2H), 7.55 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 544.

EXAMPLE 1443-{[5-(Bromomethyl)-1,3-dimethyl-1H-pyrazol-4-yl]oxy}-5-chlorobenzonitrile

N-Bromosuccinimide (340 mg, 1.90 mmol) was added to a stirred solutionof the pyrazole of Example 112 (500 mg, 1.90 mmol) in carbontetrachloride (10 ml) and azobisisobutyronitrile (20 mg) at roomtemperature under nitrogen. The reaction was heated under reflux for 1hour, cooled to room temperature and concentrated under reducedpressure. The crude product was purified by flash column chromatographyon silica gel eluting with pentane:ethyl acetate (80:20, by volume) toprovide the title compound (340 mg) as a white solid, m.p. 76-78° C.

¹H-NMR (300 MHz, CDCl₃): δ=2.03 (s, 3H), 3.45 (s, 3H), 4.32 (s, 2H),7.12 (s, 1H), 7.19 (s, 1H), 7.34 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 342.

EXAMPLE 145 3-[(3,5-Diethyl-1-methyl-1H-pyrazol-4-yl)oxy]benzonitrile

Sodium hydride (60% dispersion in oil, 22 mg, 0.53 mmol) was added to asolution of the pyrazole from Example 60 (100 mg, 0.41 mmol) and methyliodide (34 μl, 0.53 mmol) in dimethylformamide (1.5 ml) at 0° C. undernitrogen. The reaction was allowed to warm to room temperature and wasstirred for 4 hours. The reaction was quenched with water and thesolvent was removed under reduced pressure. The residue was partitionedbetween ethyl acetate (20 ml) and water (10 ml) and the organic phasewas washed with water (2×10 ml), dried over magnesium sulphate andconcentrated under reduced pressure. The residual oil was purified byflash chromatography on silica gel eluting with a solvent gradient of100% pentane changing to 100% ethyl acetate and finally ethylacetate:methanol (10:1, by volume) to provide the title compound (65 mg)as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.09 (t, 3H), 1.12 (t, 3H), 2.41 (q, 2H),2.50 (q, 2H), 3.77 (s, 3H), 7.12-7.38 (m, 4H).

LRMS (electrospray): m/z [MH⁺] 256, [MNa⁺] 278.

Microanalysis: Found C, 70.15; H, 6.78; N, 16.42. C₁₅H₁₅N₃O.0.08H₂Orequires C, 70.17; H, 6.74; N, 16.37%.

EXAMPLE 1463-{[3,5-Diethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]oxy}benzonitrile

Sodium hydride (60% dispersion in oil, 22 mg, 0.54 mmol) was added to asolution of the pyrazole from Example 60 (100 mg, 0.41 mmol) and1-bromo-2-methoxy-ethane (51 μl, 0.54 mmol) in dimethylformamide (1.5ml) at 0° C. under nitrogen. The reaction was allowed to warm to roomtemperature and was stirred for 4 hours. The reaction was quenched withwater and the solvent was removed under reduced pressure. The residuewas partitioned between ethyl acetate (20 ml) and water (10 ml) and theorganic phase was washed with water (2×10 ml), dried over magnesiumsulphate and concentrated under reduced pressure. The residual oil waspurified by flash chromatography on silica gel eluting with a solventgradient of 100% pentane changing to 100% ethyl acetate and finallyethyl acetate:methanol (90:10, by volume) to provide the title compound(66 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.09 (t, 3H), 1.12 (t, 3H), 2.42 (q, 2H),2.54 (q, 2H), 3.34 (s, 3H), 3.75 (t, 2H), 4.16 (t, 2H), 7.11-7.38 (m,4H).

LRMS (electrospray): m/z [MH⁺] 300, [MNa⁺] 322.

Microanalysis: Found C, 68.21; H, 7.07; N, 14.04. C₁₇H₂₁N₃O₂ requires C,67.85; H, 7.12; N, 14.09%.

EXAMPLE 1473-({5-[2-(Benzyloxy)ethyl]-3-ethyl-1H-pyrazol-4-yl}oxy)-5-fluorobenzonitrile

Hydrazine hydrate (390 μl, 8.00 mmol) was added to a solution of theenol from Preparation 60 (2.47 g, 6.69 mmol) in acetic acid (5 ml) undernitrogen at room temperature. After stirring for 18 hours, the mixturewas concentrated under reduced pressure and purified by flashchromatography on silica gel eluting with pentane:ethyl acetate (70:30changing to 50:50, by volume) to provide the title compound (5.8 g) as ayellow oil.

¹H NMR (400 MHz, CDCl₃): δ=1.13 (t, 3H), 2.41 (q, 2H), 2.67 (t, 2H),3.62 (t, 2H), 4.48 (s, 2H), 6.79 (m, 1H), 6.98 (m, 2H), 7.24 (m, 5H).

LRMS (electrospray): m/z [M-H⁺] 364.

Microanalysis: Found C, 66.96; H, 5.62; N, 11.25. C₂₁H₂₀N₃O₂F.0.60H₂Orequires C, 67.04; H, 5.68; N, 11.17%.

EXAMPLE 1483-{[3-Ethyl-5-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-fluorobenzonitrile

Iron(III)chloride (9.30 g, 57.5 mmol) was added to a solution of thepyrazole from Example 147 (2.10 g, 5.75 mmol) in dichloromethane (90 ml)under nitrogen at room temperature. After stirring for 20 minutes themixture was diluted with dichloromethane (50 ml), washed with water (100ml) then saturated aqueous sodium ethylenediaminetetraacetate solution(70 ml), dried over magnesium sulphate and concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with dichloromethane:methanol (98:2 changing to 95:5, by volume)to provide the title compound (1.2 g) as a brown oil which solidified onstanding.

¹H NMR (400 MHz, CDCl₃): δ=1.16 (t, 3H), 2.44 (q, 2H), 2.63 (t, 2H),3.82 (t, 2H), 6.82 (m, 1H), 6.98 (m, 2H).

LRMS (electrospray): m/z [MH⁺] 276.

Microanalysis: Found C, 60.69; H, 5.12; N, 15.08. C₁₄H₁₄N₃O₂F requiresC, 61.08; H, 5.13; N, 15.26%.

EXAMPLE 1493-({5-[2-(4-Cyanophenoxy)ethyl]-3-ethyl-1H-pyrazol-4-yl}oxy)-5-fluorobenzonitrile

4-Hydroxy-benzonitrile (49 mg, 0.41 mmol), triphenylphosphine (106 mg,0.41 mmol) and diethylazodicarboxylate (65 μl, 0.41 mmol) were addedsequentially to a solution of the alcohol from Example 148 (74 mg, 0.27mmol) in tetrahydrofuran (2 ml) under nitrogen at 0° C. The reaction wasallowed to warm to room temperature and was stirred for 18 hours. Themixture was concentrated under reduced pressure and purified by flashchromatography on silica gel eluting with toluene:ethyl acetate (75:25,by volume) to provide the title compound (50 mg) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=1.18 (t, 3H), 2.49 (q, 2H), 2.98 (t, 2H),4.21 (t, 2H), 6.82 (m, 3H), 6.99 (m, 2H), 7.56 (m, 2H).

LRMS (electrospray): m/z [MH⁺] 377.

EXAMPLES 150-152

The preparations of the following tabulated Examples of the generalformula

were performed by a similar method to that of Example 149 using theappropriate aryl alcohol as the starting material.

Starting Material Example Example No. No. R Analytical Data 150¹ 148

¹H NMR (400 MHZ, CDCl₃): δ = 1.18 (t, 3 H), 2.42 (s, 3 H), 2.52 (q, 2H), 2.99 (t, 2 H), 4.18 (t, 2 H), 6.83 (m, 1 H), 6.99 (m, 4 H), 8.04 (m,1 H). LRMS (thermospray): m/z [MH⁺] 367. 151¹ 148

¹H NMR (400 MHz, CDCl₃): δ = 1.19 (t, 3 H), 2.50 (q, 2 H), 2.98 (t, 2H), 4.22 (t, 2 H), 6.85 (m, 1 H), 6.99 (m, 2 H), 7.12 (m, 1 H), 7.18 (m,1 H), 8.22 (m, 2 H). LRMS (thermospray): m/z [MH⁺] 353. 152¹ 148

¹H NMR (400 MHz, CDCl₃): δ = 1.20 (t, 3 H), 2.53 (q, 2 H), 2.98 (t, 2H), 4.19 (t, 2 H), 4.85 (brs, 2 H), 6.58 (m, 1 H), 6.83 (m, 2 H), 6.99(m, 2 H), 7.63 (d, 1 H). LRMS (thermospray) m/z [MH⁺] 368. ¹Thesecompounds were purified on silica gel eluting with a solvent gradient ofcyclohexane: ethyl acetate (75:25 then 66:34 then 50:50, by volume)changing to ethyl acetate and finally ethyl acetate: methanol (90:10, byvolume).

EXAMPLE 1535-({5-[2-(benzyloxy)ethyl]-3-ethyl-1H-pyrazol-4-yl}oxy)isophthalonitrile

Hydrazine hydrate (177 μl, 3.66 mmol) was added to a solution of thecrude enol from Preparation 61 (917 mg, 2.40 mmol) in acetic acid (10ml) under nitrogen at room temperature. After stirring for 18 hours, themixture was concentrated under reduced pressure and purified by flashchromatography on silica gel eluting with pentane:cyclohexane (75:25, byvolume) changing to toluene:ethyl acetate (50:50, by volume) to give theproduct which was further purified by preparative HPLC using a Develosilcombi-rp C30 50×4.6 mm 3 μm column eluting with a solvent gradient of5:95 0.1% aqueous trifluoroacetic acid in water:acetonitrile to providethe title compound (5 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.18 (t, 3H), 2.44 (q, 2H), 2.77 (t, 2H),3.63 (t, 2H), 4.52 (s, 2H), 7.30 (m, 7H), 7.55 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 231, [MNa⁺] 253.

EXAMPLE 1545-{[3-Ethyl-5-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile

Iron(III)Chloride (217 mg, 1.30 mmol) was added to a solution of thepyrazole from Example 153 (50 mg, 0.13 mmol) in dichloromethane (5 ml)under nitrogen at room temperature. After stirring for 30 minutes themixture was diluted with dichloromethane (20 ml), washed with water (100ml) then saturated aqueous sodium ethylenediaminetetraacetate solution(20 ml), dried over magnesium sulphate and concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with dichloromethane:methanol (98:2 changing to 95:5, by volume)to provide the title compound (20 mg) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ=1.19 (t, 3H), 2.51 (q, 2H), 2.69 (t, 2H),3.88 (t, 2H), 7.40 (s, 2H), 7.59 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 283.

EXAMPLE 1553-{[5-(Aminomethyl)-1-(2-hydroxyethyl)-3-methyl-1H-pyrazol-4-yl]oxy}-5-chlorobenzonitrile

The protected alcohol from Preparation 31 (100 mg, 0.23 mmol) andtert-butyl-ammonium fluoride (360 μl of a 1M solution intetrahydrofuran, 0.36 mmol) were stirred in dichloromethane (5 ml) atroom temperature under nitrogen for 3 hours. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inmethanol (2 ml) and purified on a BondElut® SCX polymer supportedsulphonic acid column washing with methanol (2×3 ml) to removeimpurities and 2N aqueous ammonia to remove the product. This procedurewas repeated twice to provide the title compound (40 mg) as a colourlessoil.

¹H NMR (400 MHz, CD₃OD): δ=1.99 (s, 3H), 3.85 (t, 2H), 4.02 (s, 2H),4.32 (t, 2H), 7.22 (s, 1H), 7.28 (s, 1H), 7.47 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 309.

Microanalysis: Found C, 53.32; H, 5.17; N, 16.38. C₁₄H₁₅ClN₄O₂.0.85CH₃OHrequires C, 53.40; H, 5.55; N, 16.77%.

EXAMPLE 1565-[(1-Allyl-3-tert-butyl-5-methyl-1H-pyrazol-4-yl)oxy]isophthalonitrile

Sodium hydride (60% dispersion in oil, 120 mg, 3.15 mmol) was added to asolution of the pyrazole from Example 130 (800 mg, 2.80 mmol) and allylbromide (345 mg, 2.80 mmol) in dimethylformamide (30 ml) at roomtemperature under nitrogen and the reaction was stirred for 3 hours. Thereaction was diluted with ethyl acetate (50 ml), washed with water (2×50ml) then brine (50 ml) and the organic phase was concentrated underreduced pressure. The residual oil was purified by flash chromatographyon silica gel eluting with a solvent gradient of pentane changing toethyl acetate:pentane (20:80, by volume) to provide the title compound(600 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.21 (s, 9H), 1.96 (s, 3H), 4.66 (s, 2H),5.04 (d, 1H), 5.24 (d, 1H), 5.98 (m, 1H), 7.37 (s, 2H), 7.57 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 322.

Microanalysis: Found C, 70.79; H, 6.29; N, 17.11. C₁₉H₂₀N₄O.0.05CH₂Cl₂requires C, 70.48; H, 6.24; N, 17.26%.

EXAMPLE 1575-{[3-tert-Butyl-1-(2-hydroxyethyl)-5-methyl-1H-pyrazol-4-yl]oxy}isophthalonitrile

Sodium periodate (1.00 g, 4.60 mmol), osmium tetroxide (1.5% solution intert-butanol, 190 mg, 0.02 mmol) and the pyrazole from Example 156 (600mg, 1.86 mmol) were dissolved in acetone (9 ml) and water (3 ml) undernitrogen at room temperature, and the reaction was stirred for 5 hours.The acetone was removed under reduced pressure and the residue wasextracted with ethyl acetate (30 ml). The organic phase was washed withwater (2×30 ml) then brine (30 ml), dried over magnesium sulphate andconcentrated under reduced pressure. The crude aldehyde was thendissolved in methanol (15 ml) and sodium borohydride (84 mg, 2.22 mmol)was added portionwise at room temperature under nitrogen. The reactionwas stirred for 3 hours and the solvent was removed under reducedpressure. The residue was partitioned between ethyl acetate (10 ml) andwater (10 ml) and the organic phase was washed with water (2×10 ml) thenbrine (10 ml), dried over magnesium sulphate and concentrated underreduced pressure. The residual oil was purified by flash chromatographyon silica gel eluting with a solvent gradient of pentane changing toethyl acetate:pentane (50:50, by volume) to provide the title compound(250 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.17 (s, 9H), 1.98 (s, 3H), 3.67 (s, 1H),4.04 (m, 4H), 7.35 (s, 2H), 7.54 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 325.

Microanalysis: Found C, 64.30; H, 6.10; N, 16.35. C₁₈H₂₀N₄O₂.0.20CH₂Cl₂requires C, 64.04; H, 6.02; N, 16.41%.

EXAMPLE 1585-{[1-(2-Aminoethyl)-3-tert-butyl-5-methyl-1H-pyrazol-4-yl]oxy}isophthalonitrile

Diphenylphosphorylazide (305 mg, 1.10 mmol) was dissolved intetrahydrofuran (5 ml) and added to a solution of the pyrazole fromExample 157 (180 mg, 0.55 mmol), triphenylphosphine (291 mg, 1.10 mmol)and diethylazodicarboxylate (193 mg, 1.10 mmol) in tetrahydrofuran (20ml) under nitrogen at room temperature. The reaction was stirred for 18hours then triphenylphosphine (291 mg, 1.10 mmol) was added, and thereaction was stirred for a further 18 hours. Water (180 μl, 10.0 mmol)was then added and the reaction was stirred for 64 hours. The solventwas removed under reduced pressure and the residual white paste waspurified by flash chromatography on silica gel eluting withdichloromethane:methanol:0.88 ammonia (95:4.5:0.5, by volume) to providethe title compound (55 mg) as a colourless oil.

¹H NMR (300 MHz, CDCl₃): δ=1.22 (s, 9H), 1.78 (s, 2H), 2.03 (s, 3H),3.18 (t, 2H), 4.05 (m, 2H), 7.38 (s, 2H), 7.58 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 324.

Microanalysis: Found C, 64.46; H, 6.48; N, 20.47. C₁₈H₂₁N₅O.0.20CH₂Cl₂requires C, 64.22; H, 6.34; N, 20.57%.

EXAMPLE 1593-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-(1H-1,2,4-triazol-1-yl)benzonitrile

Cesium carbonate (179 mg, 0.55 mmol) was added to a solution of1H[1,2,4]triazole (38 mg, 0.55 mmol) in dimethylsulfoxide (1 ml) undernitrogen at room temperature and the reaction was stirred for 10minutes. The aryl fluoride from Preparation 62 (210 mg, 0.5 mmol)dissolved in dimethylsulfoxide (1 ml) was then added and the reactionwas heated to 100° C. for 18 hours. After cooling to room temperaturethe reaction was diluted with water (15 ml) and extracted with ethylacetate (25 ml). The organic phase was washed with brine (15 ml), driedover magnesium sulphate, concentrated under reduced pressure and theresidue was purified by flash chromatography on silica gel eluting witha solvent gradient of dichloromethane:methanol (98:2 changing to 90:10,by volume) to provide the title compound (67.5 mg) as a white solid,m.p. 122-124° C.

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.39 (q, 2H), 2.51 (q, 2H),3.61 (brs, 1H), 4.04 (m, 2H), 4.07 (m, 2H), 7.10 (s, 1H), 7.52 (s, 1H),7.60 (s, 1H), 8.07 (s, 1H), 8.54 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 353.

Microanalysis: Found C, 60.69; H, 5.83; N, 22.98. C₁₈H₂₀N₆O₂.0.08CH₂Cl₂requires C, 60.46; H, 5.66; N, 23.40%.

EXAMPLES 160-162

The preparation of the following tabulated Examples of the generalformula

were performed by a similar method to that of Example 159 using theappropriate heterocycle as the starting material.

Example No. (Starting Material Preparation No) R Analytical Data 160(62)

¹H NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6 H), 2.39 (q, 2 H), 2.52 (q, 2H), 3.62 (brs, 1 H), 4.02 (t, 2 H), 4.08 (t, 2 H), 6.44 (d, 2 H), 7.14(s, 1 H), 7.16 (s, 1 H), 7.25 (s, 1 H), 7.49 (d, 2 H). m.p. 169-170° C.LRMS (thermospray): m/z [MH⁺] 379. Microanalysis: Found C, 65.68; H,5.98; N, 14.31. C₂₁H₂₂N₄O₃. 0.09 CH₂Cl₂ requires C, 65.61; H, 5.79; N,14.51%. 161¹ (62)

¹H NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6 H), 2.40 (q, 2 H), 2.51 (q, 2H), 3.56 (t, 1 H), 4.04 (m, 2 H), 4.07 (m, 2 H), 7.20 (s, 1 H), 7.65 (s,2 H), 7.85 (s, 1 H), 7.98 (s, 1 H). LRMS (thermospray): m/z [MH⁺] 353.HRMS: [MH⁺] 353.1722. C₁₈H₂₀ N₆O₂ requires 353.1720. 162¹ (62)

¹H NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6 H), 2.41 (q, 2 H), 2.51 (q, 2H), 3.62 (t, 1 H), 4.04 (m, 2 H), 4.07 (m, 2 H), 7.08 (s, 1 H), 7.80 (s,2 H), 7.87 (s, 1 H), 8.02 (s, 1 H). LRMS (thermospray) m/z [MH⁺] 353.HRMS: [MH⁺] 353.1719. C₁₈H₂₀N₆O₂ requires 353.1720. ¹Both of thesecompounds were isolated from a single reaction starting from 12,3-triazole with Example 161 being the most polar.

EXAMPLE 1633-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-fluorobenzamide

The protected alcohol from Preparation 64 (432 mg, 1.07 mmol) andp-toluene-sulphonic acid (30.3 mg, 0.11 mmol) were dissolved in methanol(4 ml) and stirred under nitrogen at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between saturated aqueous sodium bicarbonate solution (20ml) and dichloromethane (20 ml). The aqueous phase was extracted withdichloromethane (10 ml) and the combined organic extracts were driedover magnesium sulphate, concentrated under reduced pressure and theresidue was purified by flash chromatography on silica gel eluting witha solvent gradient of dichloromethane:methanol (100:0 changing to 93:7,by volume) to provide the title compound (241 mg) as a white foam.

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.39 (q, 2H), 2.49 (q, 2H),3.68 (brs, 1H), 4.04 (m, 4H), 5.59 (brs, 1H), 5.88 (brs, 1H), 6.71 (d,1H), 7.11 (m, 2H).

LRMS (thermospray): m/z [MH⁺] 322.

Microanalysis: Found C, 57.91; H, 6.32; N, 12.56.C₁₆H₂₀FN₃O₃.0.13CH₂Cl₂.0.12H₂O requires C, 57.91; H, 6.18; N, 12.56%.

EXAMPLES 164-167

The preparation of the following tabulated Examples of the generalformula

were performed by a similar method to that of Example 163 using theappropriate protected alcohol as the starting material.

Example No. (Starting Material Preparation No) R Analytical Data 164¹(65)

¹H NMR (400 MHz, CDCl₃): δ = 1.13 (m, 6 H), 2.44 (q, 2 H), 2.54 (q, 2H), 3.65 (brs, 1 H), 4.07 (t, 2 H), 4.11 (t, 2 H), 6.51 (s, 1 H), 7.00(s, 1 H), 7.56 (s, 1 H), 7.63 (s, 1 H), 7.74 (s, 1 H), 7.90 (s, 1 H).LRMS (electrospray): m/z [MH⁺] 352, [MNa⁺] 374. HRMS: [MH⁺] Found352.1770. C₁₉H₂₂N₅O₂ requires 352.1768. 165¹ (66)

¹H NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6 H), 2.40 (q, 2 H), 2.50 (q, 2H), 4.00 (t, 2 H), 4.06 (t, 2 H), 6.24 (t, 1 H), 6.60 (d, 1 H), 7.18 (d,2 H), 7.24 (d, 1 H), 7.30 (s, 1 H), 7.38 (t, 1 H). LRMS (electrospray):m/z [MH⁺] 379, [MNa⁺] 401. HRMS: [MH⁺] Found 379.1766. C₂₁H₂₃N₄O₃requires 379.1765 [MNa⁺] Found 401.1585. C₂₁H₂₂N₄O₃Na requires 401.1584.166¹ (67)

¹H NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6 H), 2.41 (q, 2 H), 2.51 (q, 2H), 4.01 (t, 2 H), 4.06 (t, 2 H), 7.07 (d, 1 H), 7.13 (s, 1 H), 7.22 (m,1 H), 7.52 (s, 1 H), 7.65 (s, 1 H), 7.88 (s, 1 H). LRMS (electrospray):m/z [MH⁺] 380, [MNa⁺] 402. HRMS: [MH⁺] Found 380.1722. C₂₀H₂₂ N₅O₃requires 380.1717. 167² (68)

¹H NMR (400 MHz, CDCl₃): δ = 1.11 (m, 6 H), 2.27 (s, 3 H), 2.41 (q, 2H), 2.50 (q, 2 H), 3.70 (s, 3 H), 4.04 (t, 1 H), 4.08 (t, 2 H), 5.64 (s,1 H), 6.81 (s, 1 H), 6.91 (s, 1 H), 6.99 (s, 1 H). LRMS (electrospray):m/z [MH⁺] 396, [MNa⁺] 418. HRMS: [MH⁺] Found 396.2027. C₂₁H₂₆N₅O₃requires 396.2030. ¹The eluent used for flash column chromatographypurification of these compounds was dichloromethane: methanol (99:1changing to 80:20, by volume). ²The eluent used for flash columnchromatography purification of this compound was dichloromethane:methanol (99:1 changing to 98:2, by volume).

EXAMPLE 1685-{[3-Cyclopropyl-5-ethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile

and

EXAMPLE 1695-{[5-Cyclopropyl-3-ethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile

Potassium carbonate (91 mg, 0.66 mmol) and2-(2-bromoethoxy)-tetrahydropyran (91 μl, 0.61 mmol) were sequentiallyadded to a solution of the pyrazole from Example 129 (152 mg, 0.55 mmol)dissolved in dimethylformamide (4 ml) and the reaction was heated to 35°C. under nitrogen for 5 hours. Starting material still remained, so thetemperature was increased to 80° C. and the reaction was stirred for afurther 18 hours. The reaction was cooled to room temperature, sodiumhydride (60% dispersion in oil, 24 mg, 0.60 mmol) was added and thereaction was stirred at room temperature for 1 hour. The mixture wasdiluted with water (50 ml) and extracted with ethyl acetate (2×50 ml).The combined organic extracts were washed with brine (30 ml), dried overmagnesium sulphate, concentrated under reduced pressure and the residuewas purified by flash chromatography on silica gel eluting withpentane:cyclohexane (75:25, by volume) to provide a mixture ofregioisomers (239 mg). The regioisomers (239 mg, 0.55 mmol) andp-toluenesulphonic acid (10 mg, 0.05 mmol) were dissolved in methanol (5ml) and stirred under nitrogen at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between saturated aqueous sodium bicarbonate solution (20ml) and dichloromethane (30 ml). The organic phase was dried overmagnesium sulphate, concentrated under reduced pressure and the residualoil was purified by flash chromatography on silica gel eluting withtoluene:ethyl acetate (50:50, by volume) to yield two products ascolourless oils.

Least Polar Fraction (Example 168)—34 mg

¹H NMR (400 MHz, CDCl₃): δ=0.76 (m, 4H), 1.05 (t, 3H), 1.45 (m, 1H),2.48 (q, 2H), 3.39 (brs, 1H), 4.02 (m, 4H), 7.39 (s, 2H), 7.56 (s, 1H).

LRMS (electrospray): m/z [M-H⁺] 321.

Most Polar Fraction (Example 169)—9 mg

¹H NMR (400 MHz, CDCl₃): δ=0.62 (m, 2H), 0.78 (m, 2H), 1.18 (t, 3H),1.46 (m, 1H), 2.38 (q, 2H), 3.42 (brs, 1H), 4.02 (m, 2H), 4.21 (t, 2H),7.38 (s, 2H), 7.57 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 323, [MH⁺] 321.

EXAMPLE 1705-{[5-Ethyl-1-(2-hydroxyethyl)-3-isopropyl-1H-pyrazol-4-yl]oxy}isophthalonitrile

2-(2-Bromoethoxy)-tetrahydropyran (91 μl, 0.60 mmol) was added to asolution of the pyrazole from Example 131 (153 mg, 0.55 mmol) dissolvedin dimethylformamide (4 ml) at room temperature under nitrogen, thensodium hydride (60% dispersion in oil, 24 mg, 0.60 mmol) was added andthe reaction was stirred at room temperature for 3 hours. The mixturewas diluted with water (50 ml) and extracted with ethyl acetate (2×50ml). The combined organic extracts were washed with brine (30 ml), driedover magnesium sulphate, concentrated under reduced pressure and theresidue was purified by flash chromatography on silica gel eluting withtoluene:ethyl acetate (85:15, by volume) to provide the separatedisomers as colourless oils (83 mg of Isomer 1, 55 mg of Isomer 2).

The least polar isomer (isomer 1) (83 mg, 0.20 mmol) andp-toluene-sulphonic acid (4 mg, 0.02 mmol) were dissolved in methanol (5ml) and stirred under nitrogen at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between water (30 ml) and dichloromethane (30 ml). Theaqueous phase was extracted with dichloromethane (20 ml) and thecombined organic extracts were dried over magnesium sulphate,concentrated under reduced pressure and the residual oil was purified byflash chromatography on silica gel eluting with toluene:ethyl acetate(66:34, by volume) to provide the title compound (39 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.05 (t, 3H), 1.14 (d, 6H), 2.44 (q, 2H),2.68 (sept, 1H), 3.77 (brs, 1H), 4.06 (m, 4H), 7.38 (s, 2H), 7.58 (s,1H).

LRMS (electrospray): m/z [MH⁺] 325.

EXAMPLE 1715-{[3-Ethyl-1-(2-hydroxyethyl)-5-isopropyl-1H-pyrazol-4-yl]oxy}isophthalonitrile

The most polar isomer (isomer 2) from Example 170 (55 mg, 0.13 mmol) andp-toluene-sulphonic acid (3 mg, 0.01 mmol) were dissolved in methanol (5ml) and stirred under nitrogen at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between water (30 ml) and dichloromethane (30 ml). Theaqueous phase was extracted with dichloromethane (20 ml) and thecombined organic extracts were dried over magnesium sulphate,concentrated under reduced pressure and the residual oil was purified byflash chromatography on silica gel eluting with toluene:ethyl acetate66:33, by volume) to provide the title compound (39 mg) as a whitesolid.

¹H NMR (400 MHz, CDCl₃): δ=1.08 (t, 3H), 1.13 (d, 6H), 2.49 (q, 2H),2.97 (sept, 1H), 3.59 (t, 1H), 4.06 (m, 4H), 7.37 (s, 2H), 7.57 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 325.

EXAMPLE 172 2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethylcarbamate

Trichloroacetyl-isocyanate (46 μl, 0.38 mmol) was added to a solution ofthe alcohol from Example 119 (100 mg, 0.32 mmol) dissolved indichloromethane (3.2 ml) under nitrogen at 0° C. After stirring for 2hours the dichloromethane was removed under reduced pressure andmethanol (1.6 ml), water (1.6 ml) and potassium carbonate (134 mg, 0.96mmol) were added and the reaction was stirred for a further 2 hours. Themethanol was removed under reduced pressure and the residue wasextracted with dichloromethane (3×10 ml). The combined organic extractswere dried over magnesium sulphate, concentrated under reduced pressureand the residual solid was purified by flash chromatography on silicagel eluting with dichloromethane:methanol (98:2, by volume) to providethe title compound (60 mg) as a white solid

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.39 (q, 2H), 2.48 (q, 2H),4.26 (m, 2H), 4.44 (m, 2H), 4.62 (brs, 2H), 7.41 (s, 2H), 7.58 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 354.

Microanalysis: Found C, 60.00; H, 5.55; N, 19.82. C₁₈H₁₉N₅O₃.0.23EtOAcrequires C, 60.30; H, 5.67; N, 18.58%.

EXAMPLE 173N-{2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl}sulfamide

Sulfamide (31 mg, 0.32 mmol) was added to a solution of the amine fromExample 127 (100 mg, 0.32 mmol) dissolved in dioxan (0.5 ml) undernitrogen at room temperature. The reaction was heated to 100° C. for 18hours, cooled to room temperature and partitioned between ethyl acetate(15 ml) and water (15 ml). The organic phase was dried over magnesiumsulphate, concentrated under reduced pressure and the residual brown oilwas purified by flash chromatography on silica gel eluting withdichloromethane:methanol:0.88 ammonia (95:5:0.5, by volume) to providethe title compound (25 mg) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ=1.12 (m, 6H), 2.39 (q, 2H), 2.51 (q, 2H),3.61 (m, 2H), 4.20 (m, 2H), 4.78 (s, 2H), 5.42 (s, 1H), 7.40 (s, 2H),7.59 (s, 1H).

Microanalysis: Found C, 50.33; H, 5.07; N, 20.60. C₁₇H₂₀N₆O₃S.0.95H₂Orequires C, 50.35; H, 5.44; N, 20.72%.

EXAMPLE 174N-{2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl}-2-methoxyacetamide

The amine from Example 127 (100 mg, 0.32 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (68 mg, 0.35mmol) and N,N-dimethylaminopyridine (43 mg, 0.35 mmol) were added to asolution of 1-methoxyacetic acid (27 μl, 0.35 mmol) dissolved indichloromethane (10 ml) under nitrogen at room temperature. The reactionwas stirred for 18 hours, concentrated under reduced pressure and theresidual yellow oil was purified by flash chromatography on silica geleluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5, by volume)to provide the title compound (32 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.11 (t, 3H), 1.16 (t, 3H), 2.38 (q, 2H),2.47 (q, 2H), 3.41 (s, 3H), 3.77 (dd, 2H), 3.89 (s, 2H), 4.15 (m, 2H),7.19 (brs, 1H), 7.40 (s, 2H), 7.59 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 382.

Microanalysis: Found C, 61.26; H, 6.18; N, 17.59. C₂₀H₂₃N₅O₃.0.60H₂Orequires C, 61.24; H, 6.22; N, 17.85%.

EXAMPLE 1755-{[1-(3-Azetidinyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}isophthalonitrile

The protected amine from Preparation 69 (178 mg, 0.42 mmol) wasdissolved in 4M hydrochloric acid in dioxan solution (1 ml) and dioxan(1 ml) and the reaction was stirred at room temperature for 18 hours.The solvent was removed under reduced pressure and the residue waspartitioned between dichloromethane (20 ml) and saturated aqueous sodiumbicarbonate solution (20 ml). The organic phase was dried over magnesiumsulphate, concentrated under reduced pressure and purified by flashchromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol:0.88 ammonia (100:0:0 then 98:2:0 then 95:5:0then 95:5:0.5 then 90:10:1 then 80:20:1, by volume) to provide the titlecompound (33 mg) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ=1.05 (t, 3H), 1.11 (t, 3H), 2.44 (m, 4H),3.85 (m, 2H), 4.38 (m, 2H), 5.05 (m, 1H), 7.37 (s, 2H), 7.56 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 322.

Microanalysis: Found C, 65.87; H, 5.94; N, 20.98. C₁₈H₁₉N₅O.0.38H₂Orequires C, 65.87; H, 6.07; N, 21.04%.

EXAMPLE 1765-{[3,5-Diethyl-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile

The protected alcohol from Preparation 70 (215 mg, 0.53 mmol) andp-toluene-sulphonic acid (10 mg, 0.05 mmol) were dissolved in methanol(2 ml) and stirred under nitrogen at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between water (10 ml) and dichloromethane (10 ml). Theorganic phase was dried over magnesium sulphate and concentrated underreduced pressure to provide the title compound (148 mg) as a pale yellowsolid, m.p. 93-95° C.

¹H NMR (400 MHz, CDCl₃): δ=1.11 (m, 6H), 2.04 (tt, 2H), 2.37 (q, 2H),2.53 (q, 2H), 3.06 (t, 1H), 3.69 (dt, 2H), 4.18 (t, 2H), 7.38 (s, 2H),7.58 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 325, [MNa⁺] 347.

Microanalysis: Found C, 66.27; H, 6.27; N, 17.00. C₁₀H₂₀N₄O₂ requires C,66.28; H, 6.24; N, 17.18%.

EXAMPLE 1775-[(3,5-Diethyl-1-methyl-1H-pyrazol-4-yl)oxy]isophthalonitrile

Sodium hydride (60% dispersion in oil, 33 mg, 0.82 mmol) was added to asolution of the pyrazole from Example 122 (200 mg, 0.75 mmol) indimethylformamide (3 ml) at 0° C. under nitrogen and the reaction wasstirred for 10 minutes. Methyl iodide (117 mg, 0.82 mmol) was added andthe reaction was stirred at room temperature for 18 hours. The reactionwas quenched with water (0.2 ml) and concentrated under reducedpressure. The residue was partitioned between dichloromethane (5 ml) andwater (5 ml) and the organic phase was isolated using a 5 μM WhatmanPTFE fritted cartridge, then concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting witha solvent gradient of ethyl acetate:pentane (20:80, by volume) changingto ethyl acetate:methanol (90:10, by volume) thendichloromethane:methanol:0.88 ammonia (90:10:1 then 80:20:1, by volume)to provide the title compound (170 mg) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.39 (q, 2H), 2.49 (q, 2H),3.80 (s, 3H), 7.40 (s, 2H), 7.56 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 281.

Microanalysis: Found C, 68.41; H, 5.71; N, 19.93. C₁₆H₁₆N₄O requires C,68.55; H, 5.75; N, 19.99%.

EXAMPLES 178-180

The preparation of the following tabulated Examples of the generalformula

were performed by a similar method to that of Example 177 using theappropriate alkyl halide as the starting material.

Example No. (Starting Material Example No.) R Analytical Data 178 (122)

¹H NMR (400 MHz, CDCl₃): δ = 1.08 (t, 3 H), 1.12 (t, 3 H), 2.40 (q, 2H), 2.54 (q, 2 H), 3.34 (s, 3 H), 3.75 (t, 2 H), 4.17 (t, 2 H), 7.38 (s,2 H), 7.56 (s, 1 H). LRMS (electrospray): m/z [MH⁺] 325, [MNa⁺] 347.Microanalysis: Found C, 65.73; H, 6.17; N, 17.08. C₁₈H₂₀N₄O₃•0.25H₂Orequires C, 65.74; H, 6.28; N, 17.04%. 179^(1,2) (122)

¹H NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6 H), 1.98 (tt, 2 H), 2.38 (q, 2H), 2.51 (q, 2 H), 2.76 (t, 2 H), 4.09 (t, 2 H), 7.38 (s, 2 H), 7.57 (s,1 H). LRMS (electrospray): m/z [MH⁺] 324. Microanalysis: Found C, 64.86;H, 6.51; N, 20.79. C₁₈H₂₁N₅O•0.57H₂O requires C, 64.79; H, 6.69; N,20.99%. 180³ (122)

¹H NMR (400 MHz, CDCl₃): δ = 1.09 (t, 3 H), 1.14 (t, 3 H), 2.41 (q, 2H), 2.47 (q, 2 H), 3.79 (s, 3 H), 4.82 (s, 2 H), 7.40 (s, 2 H), 7.57 (s,1 H). LRMS (electrospray): m/z [MH⁺] 339. Microanalysis: Found C, 63.58;H, 5.35; N, 16.35. C₁₈H₁₈N₄O₃•0.10H₂O requires C, 63.56; H, 5.39; N,16.47%. ¹The two reagents were heated together as a melt at 160° C. for24 hours, and the reaction was worked up by partitioning betweendichloromethane and saturated sodium bicarbonate solution, extractingthe organic phase with 2 M aqueous hydrochloric acid and basifying theaqueous phase with sodium carbonate. After extraction withdichloromethane the organic phase was dried and concentrated to give thecrude product. ²The eluent used for flash column chromatographypurification of this compound was dichloromethane:methanol:0.88 ammonia(95:5:0.5 changing to 80:20:1, by volume). ³The eluent used for flashcolumn chromatography purification of this compound was pentane:ethylacetate (75:25 changing to 66:34 then 50:50, by volume). ⁴Thehydrochloride salt of the starting alkyl halide was used.

EXAMPLE 1812-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetamide

The ester from Example 180 (200 mg, 0.59 mmol) was dissolved in 2Mmethanolic ammonia solution (5 ml) and the reaction was stirred undernitrogen at 75° C. for 18 hours. The mixture was concentrated underreduced pressure and the residue was purified by flash chromatography onsilica gel eluting with a solvent gradient ofdichloromethane:methanol:0.88 ammonia (95:5:0.5, by volume) to providethe title compound (6 mg).

¹H NMR (400 MHz, CDCl₃): δ=1.10 (t, 3H), 1.15 (t, 3H), 2.44 (q, 2H),2.54 (q, 2H), 4.69 (s, 2H), 5.55 (brs, 1H), 6.22 (brs, 1H), 7.38 (s,2H), 7.59 (s, 1H).

LRMS (electrospray): m/z [M-H⁺] 322.

Microanalysis: Found C, 68.41; H, 5.71; N, 19.93. C₁₆H₁₆N₄O requires C,68.55; H, 5.75; N, 19.99%.

EXAMPLE 1825-{[3,5-Diethyl-1-(hydroxymethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile

Formaldehyde (37% solution in water, 253 μl, 3.14 mmol) was added to asolution of the pyrazole from Example 122 (440 mg, 1.65 mmol) in ethanol(5 ml) and the reaction was stirred at 80° C. for 18 hours. Aftercooling to room temperature the solvent was removed under reducedpressure and the residual yellow solid was partitioned between ethylacetate (15 ml) and water (10 ml) and the organic phase was removed. Theaqueous phase was washed with ethyl acetate (2×15 ml) and the combinedorganic extracts were dried over magnesium sulphate and concentratedunder reduced pressure to provide the title compound (490 mg) as a whitesolid.

¹H NMR (400 MHz, CDCl₃): δ=1.13 (t, 3H), 1.14 (t, 3H), 2.39 (q, 2H),2.61 (q, 2H), 5.49 (s, 2H), 5.68 (brs, 1H), 7.40 (s, 2H), 7.56 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 267.

Microanalysis: Found C, 64.28; H, 5.52; N, 18.47. C₁₆H₁₆N₄O₂.0.15H₂Orequires C, 64.27; H, 5.49; N, 18.24%.

EXAMPLE 1833-[({[4-(3-cyano-5-fluorophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}amino)methyl]benzamide

The pyrazole from Preparation 75 (320 mg, 0.91 mmol) and the amine fromPreparation 80 (680 mg, 4.61 mmol) were refluxed in isopropanol (5 ml)for 1.5 hours. The solvent was removed under reduced pressure and theresidue was purified by flash chromatography on silica gel eluting withdichloromethane:methanol:0.88 ammonia (95:5:0.5, by volume) to give theproduct which was further purified by preparative HPLC using a Develosilcombi-rp C30 50×4.6 mm 3 μm column eluting with a solvent gradient of5:95 0.1% aqueous trifluoroacetic acid in acetonitrile:acetonitrile (0-6min 95:5 changing to 50:50; 6-7 min 50:50; 7-7.1 min 50:50 changing to5:95; 7.1-8 min 5:95) to provide the title compound (38 mg).

¹H NMR (400 MHz, CD₃OD): δ=2.14 (s, 3H), 4.10 (s, 2H), 4.34 (s, 2H),7.03 (m, 1H), 7.10 (s, 1H), 7.25 (m, 1H), 7.54 (t, 1H), 7.64 (d, 1H),7.92 (d, 1H), 7.97 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 380.

Microanalysis: Found C, 51.32; H, 3.91; N, 13.69.C₂H₁₈N₅O₂F.1.00CF₃CO₂H1.10H₂O requires C, 51.49; H, 4.16; N, 13.65%.

EXAMPLES 184-188

The preparation of the following tabulated Examples of the generalformula

were performed by a similar method to that of Example 183 using as thestarting materials the appropriate pyrazole (P) and amine (A).

Ex. P prep A prep no. no. no. X R Analytical Data 184¹ 75 55 F

¹H NMR (400 MHz, CDCl₃): δ = 2.09 (s, 3 H), 3.65 (s, 2 H), 3.79 (s, 2H), 6.80 (d, 1 H), 6.93 (s, 1 H), 6.97 (d, 1 H), 7.31 (d, 2 H), 7.72 (d,2 H). LRMS (thermospray): m/z [MH⁺] 380. 185¹ 76 55 CN

m.p. 114-116° C. ¹H NMR (400 MHz, CDCl₃): δ = 2.08 (s, 3 H), 3.62 (s, 2H), 3.77 (s, 2 H), 7.34 (d, 2 H), 7.55 (s, 1 H), 7.77 (d, 2 H), 7.79 (s,1 H) LRMS (thermospray): m/z [MH⁺] 387. 186¹ 18 80 Cl

m.p. 98-101° C. ¹H NMR (400 MHz, CDCl₃): δ = 2.04 (s, 3 H), 3.62 (s, 2H), 3.74 (s, 2 H), 6.97 (s, 1 H), 7.07 (s, 1 H), 7.20 (s, 1 H), 7.22 (d,1 H), 7.29 (t, 1 H), 7.62 (s, 1 H), 7.81 (s, 1 H). LRMS (thermospray):m/z [MH⁺] 396. Microanalysis: Found C, 56.98; H, 4.58; N, 17.69.C₂₀H₁₈ClN₅O₂. 0.40 CH₂Cl₂ requires C, 57.01; H, 4.41; N, 16.29%.187^(1,2,3) 77 55 Me

¹H NMR (400 MHz, CDCl₃): δ = 2.10 (s, 3 H), 2.30 (s, 3 H), 3.65 (s, 2H), 3.80 (s, 2 H), 6.85 (s, 1 H), 6.95 (s, 1 H), 7.10 (s, 1 H), 7.30 (d,2 H), 7.70 (d, 2 H). LRMS (electrospray): m/z [MH⁺] 376, [MH⁺] 374.Microanalysis: Found C, 65.59; H, 5.65; N, 18.19. C₂₁H₂₁N₅O₂. 0.50 H₂Orequires C, 65.51; H, 5.77; N, 18.22%. 188⁴ 78 55 H

¹H NMR (400 MHz, CD₃OD): δ = 2.15 (s, 3 H), 4.10 (s, 2 H), 7.20 (m, 2H), 7.40 (m, 1 H), 7.50 (m, 1 H), 7.55 (d, 2 H), 7.90 (d, 2 H).Microanalysis: Found C, 53.51; H, 4.13; N, 13.59. C₂₀H₁₉N₅O₂. 1.25 TFArequires C, 53.63; H, 4.05; N, 13.90%. ¹No preparative HPLC was requiredfor purification of this compound. ²The eluent used for flash columnchromatography purification of this compound was dichloromethane:methanol: 0.88 ammonia (95:5:0.5 changing to 90:10:1, by volume). ³Theproduct was triturated with dichloromethane containing a trace ofmethanol-a solid crystallised out which was an impurity. This wasfiltered off and the filtrate was concentrated under reduced pressureand the residue was purified by flash chromatography eluting withdichloromethane: methano: 0.88 ammonia (90:10:1, by volume) to give thetitle compound. ⁴The column used for preparative HPLC was a LUNA C18 10μm 150 × 21.2 mm.

EXAMPLE 189 5-[(3,5-Dicyclopropyl-1H-pyrazol-4-yl)oxy]isophthalonitrile

Hydrazine hydrate (133 μl, 2.75 mmol) was added to a solution of thediketone from Preparation 82 (735 mg, 2.50 mmol) in acetic acid (25 ml)under nitrogen at room temperature. After stirring for 64 hours, themixture was concentrated under reduced pressure and the residue waspartitioned between dichloromethane (25 ml) and saturated aqueous sodiumbicarbonate solution (25 ml). The organic phase was dried over magnesiumsulphate, concentrated under reduced pressure and the residue waspurified by flash chromatography on silica gel eluting withdichloromethane:methanol (98:2 changing to 96:4, by volume) to providethe title compound (473 mg) as a white solid, m.p. 168-170° C.

¹H NMR (400 MHz, CDCl₃): δ=0.77 (m, 4H), 0.85 (m, 4H), 1.59 (m, 2H),7.44 (s, 2H), 7.59 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 291.

Microanalysis: Found C, 69.90; H, 4.85; N, 19.18. C₁₇H₁₄N₄O.0.10H₂Orequires C, 69.90; H, 4.90; N, 19.18%.

EXAMPLE 1905-{[3,5-Dicyclopropyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile

2-Hydroxyethylhydrazine (84 mg, 1.10 mmol) was added to a solution ofthe diketone from Preparation 82 (294 mg, 1.00 mmol) in acetic acid (10ml) under nitrogen at room temperature. After stirring for 64 hours, themixture was concentrated under reduced pressure and the residue waspartitioned between dichloromethane (25 ml) and saturated aqueous sodiumbicarbonate solution (25 ml). The organic phase was dried over magnesiumsulphate, concentrated under reduced pressure and the residue waspurified by flash chromatography on silica gel eluting withdichloromethane:methanol (99:1 changing to 95:5, by volume) to providethe title compound (137 mg) as a white solid, m.p. 115-117° C.

¹H NMR (400 MHz, CDCl₃): δ=0.67 (m, 2H), 0.80 (m, 4H), 0.85 (m, 2H),1.52 (m, 2H), 3.39 (brs, 1H), 4.05 (m, 2H), 4.22 (t, 2H), 7.42 (s, 2H),7.58 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 355.

Microanalysis: Found C, 67.63; H, 5.55; N, 16.35. C₁₉H₁₈N₄O₂.0.17H₂Orequires C, 67.63; H, 5.48; N, 16.60%.

EXAMPLE 1915-{[1-(2-Aminoethyl)-3,5-dicyclopropyl-1H-pyrazol-4-yl]oxy}isophthalonitrile

2-Chloroethylamine hydrochloride (192 mg, 1.65 mmol) and the pyrazolefrom Example 189 (440 mg, 1.50 mmol) were heated as a melt at 160° C.for 18 hours and the residue was partitioned between dichloromethane (25ml) and 10% aqueous potassium carbonate solution (25 ml). The organicphase was dried over magnesium sulphate, concentrated under reducedpressure and the residue was purified by flash chromatography on silicagel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0 changingto 95:5:0.5, by volume) to provide the title compound (9.2 mg) as awhite solid, m.p. 175-177° C.

¹H NMR (400 MHz, CDCl₃): δ=0.70 (m, 2H), 0.79 (m, 4H), 0.88 (m, 2H),1.57 (m, 1H), 1.66 (m, 1H), 3.46 (t, 2H), 4.41 (t, 2H), 7.62 (s, 2H),7.58 (s, 1H).

EXAMPLE 1923-{[3-cyclopropyl-1-(2-hydroxyethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrile

and

EXAMPLE 1933-{[5-cyclopropyl-1-(2-hydroxyethyl)-3-methyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrile

2-Hydroxy-ethyl-hydrazine (326 μl, 4.80 mmol) was added to a solution ofthe diketone from Preparation 86 (1.00 g, 4.37 mmol) in acetic acid (10ml) under nitrogen at room temperature. After stirring for 18 hours, themixture was concentrated under reduced pressure and the residual orangeoil was purified by flash chromatography on silica gel eluting withethyl acetate:pentane (50:50 changing to 100:0, by volume) to providetwo pale yellow oils.

Least Polar Fraction (Example 192)—419 mg

¹H NMR (400 MHz, CDCl₃): δ=0.69 (m, 2H), 0.82 (m, 2H), 1.54 (m, 1H),2.00 (s, 3H), 2.35 (s, 3H), 3.46 (brs, 1H), 4.05 (t, 2H), 4.22 (t, 2H),6.88 (s, 1H), 6.94 (s, 1H), 7.08 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 298.

Microanalysis: Found C, 68.29; H, 6.51; N, 13.92. C₁₇H₁₉N₃O₂ requires C,68.67; H, 6.44; N, 14.13%.

Most Polar Fraction (Example 193)—201 mg

¹H NMR (400 MHz, CDCl₃): δ=0.75 (m, 4H), 1.58 (m, 1H), 2.07 (s, 3H),2.35 (s, 3H), 3.45 (brs, 1H), 4.00 (m, 4H), 6.92 (s, 1H), 7.00 (s, 1H),7.10 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 298.

Microanalysis: Found C, 68.44; H, 6.49; N, 13.95. C₁₇H₁₉N₃O₂ requires C,68.67; H, 6.44; N, 14.13%.

EXAMPLE 1943-[3-Cyclopropyl-1-(2-amino-ethyl)-5-methyl-1H-pyrazol-4-yloxy]-5-methyl-benzonitrile

The alcohol from Example 192 (140 mg, 0.47 mmol), triphenylphosphine(309 mg, 1.18 mmol) and phthalimide (174 mg, 1.18 mmol) were dissolvedin tetrahydrofuran (9 ml) at 0° C. under nitrogen anddiisopropylazodicarboxylate (232 μl, 1.18 mmol) dissolved intetrahydrofuran (2 ml) was added over 10 minutes. The reaction wasallowed to warm to room temperature and was stirred for 18 hours. Thesolvent was removed under reduced pressure, the residue was dissovled inethanol (11 ml) and hydrazine hydrate (114 μl, 2.35 mmol) was added. Thethick white slurry was stirred for 18 h at room temperature undernitrogen, methanol (10 ml) was added and the mixture was filtered. Thefiltrate was concentrated under reduced pressure and the residue wasdissolved in dichloromethane (20 ml). The organic phase was extractedwith 2M aqueous hydrochloric acid (20 ml) and the aqueous phase waswashed with dichloromethane (5×10 ml), basified with 1M aqueous sodiumhydroxide and extracted with dichloromethane (50 ml). The organic phasewas dried over magnesium sulphate and concentrated under reducedpressure to provide the title compound (135 mg) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=0.70 (m, 4H), 1.56 (m, 1H), 2.06 (s, 3H),2.30 (s, 3H), 3.10 (t, 2H), 3.97 (t, 2H), 6.87 (s, 1H), 6.92 (s, 1H),7.05 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 297.

Microanalysis: Found C, 63.81; H, 6.51; N, 17.30. C₁₇H₂₀N₄O.0.36CH₂Cl₂requires C, 63.78; H, 6.39; N, 17.14%.

EXAMPLE 1953-[(3-Cyclopropyl-5-methyl-1H-pyrazol-4-yl)oxy]-5-methylbenzonitrile

Hydrazine hydrate (31 μl, 0.64 mmol) was added to a solution of thediketone from Preparation 86 (150 mg, 0.58 mmol) in acetic acid (1.3 ml)under nitrogen at room temperature. After stirring for 24 hours, themixture was concentrated under reduced pressure and the residue waspurified by flash chromatography on silica gel eluting withpentane:ethyl acetate (60:40 changing to 40:60, by volume) to providethe title compound (140 mg).

¹H NMR (400 MHz, CDCl₃): δ=0.60 (m, 4H), 1.69 (m, 1H), 2.09 (s, 3H),2.34 (s, 3H), 6.95 (s, 1H), 6.99 (s, 1H), 7.10 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 254.

Microanalysis: Found C, 68.35; H, 6.13; N, 15.10. C₁₅H₁₅N₃O.0.29EtOAcrequires C, 68.72; H, 6.32; N, 14.88%.

EXAMPLE 1963-{[1-(3-Aminopropyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrile

3-Chloropropylamine hydrochloride (62 mg, 0.48 mmol) and the pyrazolefrom Example 123 (113 mg, 0.44 mmol) were heated as a melt at 150° C.for 18 hours. After cooling the residue was purified by flashchromatography on silica gel eluting with dichloromethane:methanol:0.88ammonia (98:2:0 changing to 95:5:0.5, by volume). An impurity remainedso the oil was dissolved in acetone (3 ml) and (L)-tartaric acid (54 mg,0.44 mmol) was added, the mixture was heated to effect dissolution andcooled. The resultant precipitate was isolated by filtration washingwith acetone (10 ml) to provide the title compound (127 mg) as a whitesolid which was the tartrate salt.

¹H NMR (400 MHz, CD₃OD): δ=1.05 (m, 6H), 2.07 (m, 2H), 2.37 (q, 2H),2.53 (s, 3H), 2.57 (q, 2H), 2.99 (t, 2H), 4.15 (t, 2H), 4.38 (s, 2H),6.89 (s, 1H), 7.01 (s, 1H), 7.19 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 313.

Microanalysis: Found C, 56.81; H, 6.57; N, 12.06. C₂₂H₃₀N₄O₇ requires C,57.13; H, 6.54; N, 12.11%.

EXAMPLE 1973-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-4-methoxybenzonitrile

Cesium carbonate (700 mg, 2.14 mmol) was added to a stirred solution of2-methoxy-5-cyanophenol (285 mg, 2.15 mmol) and the dione of Preparation2 (348 mg, 2.15 mmol) in acetone (20 ml) at room temperature. Thereaction was heated at 50° C. for 3 hours and then cooled to roomtemperature. The mixture was concentrated under reduced pressure,dissolved in dichloromethane (5 ml) and washed with water (5 ml). Theorganic phase was isolated using a 51M Whatman PTFE fritted cartridge,then concentrated under reduced pressure. The residue was dissolved inacetic acid (5.4 ml) and 2-hydroxy-ethyl-hydrazine (160 μl, 2.15 mmol)added under nitrogen at room temperature. After stirring for 18 hours,the mixture was concentrated under reduced pressure and the residualorange oil was purified by flash chromatography on silica gel elutingwith a solvent gradient of ethyl acetate:pentane (25:75 changing to50:50, by volume) to provide the title compound (182 mg).

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.39 (q, 2H), 2.51 (q, 2H),3.71 (brs, 1H), 4.00 (s, 3H), 4.08 (m, 2H), 4.09 (m, 2H), 6.89 (s, 1H),6.99 (d, 1H), 7.32 (d, 1H).

LRMS (thermospray): m/z [MH⁺] 316.

Microanalysis: Found C, 64.57; H, 6.73; N, 13.15. C₁₇H₂₁N₃O₃ requires C,64.74; H, 6.71; N, 13.32%.

EXAMPLES 198-199

The preparation of the following tabulated Examples of the generalformula

were performed by a similar method to that of Example 197 using theβ-diketone of Preparation 2 and the appropriate aryl alcohol as thestarting materials.

Example No. R Analytical Data 198

¹H NMR (400 MHz, CDCl₃): δ = 1.04 (m, 6 H), 2.42 (q, 2 H), 2.51 (q, 2H), 4.07 (m, 2 H), 4.12 (m, 2 H), 6.60 (d, 1 H), 7.25 (t, 1 H), 7.49 (d,1 H), 7.53 (m, 2 H), 7.82 (m, 1 H), 8.41 (m, 1 H). LRMS (thermospray):m/z [MH⁺] 311. 199

¹H NMR (400 MHz, CDCl₃): δ = 1.19 (m, 6 H), 2.48 (q, 2 H), 2.51 (q, 2H), 4.03 (m, 2 H), 4.10 (m, 2 H), 7.06 (s, 1 H), 7.22 (m, 1 H), 7.38 (t,1 H), 7.42 (m, 1 H), 7.69 (d, 1 H), 7.79 (s, 1 H), 7.80 (s, 1 H) LRMS(thermospray): m/z [MH⁺] 311. Microanalysis: Found C, 72.16; H, 7.20; N,8.95. C₁₉H₂₂N₂O₂. 0.10 EtOAc requires C, 72.45; H, 7.19; N, 8.63%.

EXAMPLE 2002-{4-[3,5-Di(1H-pyrazol-1-yl)phenoxy]-3,5-diethyl-1H-pyrazol-1-yl}ethanol

The protected alcohol from Preparation 88 (254 mg, 0.53 mmol) andp-toluene-sulphonic acid (10 mg, 0.05 mmol) were dissolved in methanol(4 ml) and stirred under nitrogen at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between saturated aqueous sodium bicarbonate solution (20ml) and dichloromethane (20 ml). The aqueous phase was extracted withdichloromethane (10 ml) and the combined organic extracts were driedover magnesium sulphate, concentrated under reduced pressure andpurified by flash chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol (100:0 changing to 93:7, by volume)to provide the title compound (56 mg) as a white solid, m.p. 108-110° C.

¹H NMR (400 MHz, CDCl₃): δ=1.11 (m, 6H), 2.46 (q, 2H), 2.53 (q, 2H),4.01 (t, 2H), 4.07 (t, 2H), 6.44 (s, 2H), 7.16 (s, 2H), 7.68 (s, 3H),7.92 (s, 2H).

LRMS (electrospray): m/z [MH⁺] 393, [MNa⁺] 415.

Microanalysis: Found C, 63.62; H, 6.11; N, 21.11. C₂₁H₂₄N₆O₂.0.06CH₂Cl₂requires C, 63.63; H, 6.12; N, 21.14%.

EXAMPLE 2012-{3,5-Diethyl-4-[3-fluoro-5-(1H-pyrazol-1-yl)phenoxy]-1H-pyrazol-1-yl}ethanol

The protected alcohol from Preparation 89 (38.6 mg, 0.09 mmol) andp-toluene-sulphonic acid (3.5 mg, 0.01 mmol) were dissolved in methanol(1 ml) and stirred under nitrogen at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between 10% aqueous potassium carbonate solution (4 ml) anddichloromethane (4 ml). The aqueous phase was extracted withdichloromethane (10 ml) and the combined organic extracts were driedover magnesium sulphate, concentrated under reduced pressure andpurified by flash chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol (99:1 changing to 98:2, by volume)to provide the title compound (23 mg) as a white solid, m.p. 120-122° C.

¹H NMR (400 MHz, CDCl₃): δ=1.14 (m, 6H), 2.46 (q, 2H), 2.55 (q, 2H),4.06 (m, 2H), 4.09 (m, 2H), 6.47 (s, 1H), 6.49 (s, 1H), 7.09 (s, 1H),7.12 (s, 1H), 7.71 (s, 1H), 7.86 (s, 1H).

LRMS (electrospray): m/z [MNa⁺] 367.

HRMS: [MH⁺] Found 345.1717. C₁₈H₂₂FN₄O₂ requires 345.1722.

EXAMPLE 2023-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-methoxybenzonitrile

The protected alcohol from Preparation 90 (400 mg, 1.00 mmol) andp-toluene-sulphonic acid (19 mg, 0.10 mmol) were dissolved in methanol(10 ml) and stirred under nitrogen at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between saturated aqueous sodium bicarbonate solution (20ml) and dichloromethane (20 ml). The aqueous phase was extracted withdichloromethane (40 ml) and the combined organic extracts were driedover magnesium sulphate, concentrated under reduced pressure andpurified by flash chromatography on a silica gel eluting withdichloromethane:methanol (97:3, by volume) to provide the title compound(174 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.09 (m, 6H), 2.40 (q, 2H), 2.49 (q, 2H),3.78 (s, 3H), 4.04 (m, 2H), 4.08 (m, 2H), 6.66 (s, 1H), 6.71 (s, 1H),6.79 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 316.

Microanalysis: Found C, 63.63; H, 6.76; N, 13.06. C₁₇H₂₁N₃O₃.0.08CH₂Cl₂requires C, 63.68; H, 6.68; N, 13.04%.

EXAMPLE 2032-[4-(3,5-Difluorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethylamine

The alcohol from Example 38 (371 mg, 1.25 mmol), triphenylphosphine (984mg, 3.75 mmol) and phthalimide (552 mg, 3.75 mmol) were dissolved intetrahydrofuran (20 ml) at 0° C. under nitrogen anddiisopropylazodicarboxylate (738 μl, 3.75 mmol) dissolved intetrahydrofuran (2 ml) was added over 10 minutes. The reaction wasallowed to warm to room temperature and was stirred for 18 hours. Thesolvent was removed under reduced pressure, the residue was dissolved inethanol (25 ml) and hydrazine hydrate (303 μl, 6.25 mmol) was added. Theslurry was stirred for 4 hours at 45° C. under nitrogen, concentratedunder reduced pressure and the residue was dissolved in methanol. Thesolution was then passed through an SCX column eluting with methanol toremove impurities, then 2M methanolic ammonia solution to elute theproduct. The product was then purified by flash chromatography onalumina eluting with dichloromethane:methanol:0.88 ammonia (90:10:1, byvolume) to provide the title compound (212 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.12 (m, 6H), 2.43 (q, 2H), 2.54 (q, 2H),3.21 (t, 2H), 4.07 (t, 2H), 6.43 (m, 3H).

Microanalysis: Found C, 59.78; H, 6.50; N, 14.35. C₁₅H₁₉F₂N₃O.0.26H₂Orequires C, 60.05; H, 6.56; N, 14.01%.

EXAMPLE 2043-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-fluorobenzamide

The alcohol from Example 163 (142 mg, 0.44 mmol), triphenylphosphine(346 mg, 1.32 mmol) and phthalimide (194 mg, 1.32 mmol) were dissolvedin tetrahydrofuran (8 ml) at 0° C. under nitrogen anddiisopropylazodicarboxylate (260 μl, 1.32 mmol) dissolved intetrahydrofuran (1 ml) was added over 10 minutes. The reaction wasallowed to warm to room temperature and was stirred for 18 hours. Thesolvent was removed under reduced pressure, the residue was dissolved inethanol (9 ml) and hydrazine hydrate (107 μl, 2.2 mmol) was added. Theslurry was stirred for 4 hours at 45° C. under nitrogen, concentratedunder reduced pressure and the residue was dissolved in methanol. Thesolution was then passed through a polymer supported sulphonic acidcolumn eluting with methanol to remove impurities, then 2M methanolicammonia solution to elute the product. The product was then purified byflash chromatography on alumina eluting withdichloromethane:methanol:0.88 ammonia (90:10:1, by volume) to providethe title compound (60 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.11 (m, 6H), 2.43 (q, 2H), 2.53 (q, 2H),3.17 (t, 2H), 4.05 (t, 2H), 6.01 (brs, 1H), 6.25 (brs, 1H), 6.75 (d,1H), 7.16 (m, 2H).

HRMS: [MH⁺] Found 321.1718. C₁₆H₂₁FN₄O₂ requires 321.1722.

EXAMPLE 2053-[(3-Isopropyl-5-methyl-1H-pyrazol-4-yl)oxy]-5-methylbenzonitrile

Hydrazine hydrate (100 μl, 2.10 mmol) was added to a solution of thediketone from Preparation 91 (544 mg, 2.10 mmol) in acetic acid (10 ml)under nitrogen at room temperature. After stirring for 64 hours, themixture was concentrated under reduced pressure and the residue waspurified by flash chromatography on silica gel eluting withpentane:ethyl acetate (66:34, by volume) to provide the title compound(308 mg) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=1.22 (d, 6H), 2.09 (s, 3H), 2.56 (s, 3H),2.84 (m, 1H), 6.91 (s, 1H), 6.94 (s, 1H), 7.11 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 256.

EXAMPLE 2063-{[1-(2-Aminoethyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrile

The pyrazole from Example 205 (70 mg, 0.27 mmol) and 2-chloroethylaminehydrochloride (38 mg, 0.33 mmol) were heated as a melt at 150° C. for 18hours. The residue was cooled and purified by flash chromatography onsilica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5,by volume) to give the title compound (25 mg).

¹H NMR (400 MHz, CDCl₃): δ=1.18 (m, 6H), 2.06 (s, 3H), 2.35 (s, 3H),2.79 (m, 1H), 3.19 (m, 2H), 4.04 (m, 2H), 6.89 (s, 1H), 6.97 (s, 1H),7.12 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 300.

EXAMPLE 2072-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N-(2-pyridinylmethyl)acetamide

Standard solutions: The acid of Preparation 4 (800 mg, 2.33 mmol),1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(822 mg, 3.50 mmol) and diisopropylethylamine (603 mg, 4.66 mmol) wereseparately dissolved in N,N-dimethylformamide (3×13 ml).2-(Methylamino)pyridine (3 mg, 0.029 mmol) was treated with the standardsolutions of the acid and coupling reagents (3×170 μl) in a 96 wellplate and the mixture was shaken for 14 hours at room temperature. Thesolvent was removed under reduced pressure and the mixture dissolved indimethylsulphoxide (500 μl) and purified by HPLC (Magellen C_(B)(2)150×10 mm column; a gradient mobile phase was used, 5:95 (by volume) to95:5 (by volume) acetonitrile:(0.1% trifluoroacetic acid in water).

Retention time: 5.69 minutes.

LRMS (electrospray): m/z [MH⁺] 434.

EXAMPLE 208[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]acetonitrile

The pyrazole of Preparation 8 (1.00 g, 2.60 mmol) in tetrahydrofuran (10ml) was added in one portion to a solution of sodium cyanide (284 mg,5.20 mmol) in water (10 ml) at room temperature. The reaction was heatedat 80° C. for 14 hours and cooled to room temperature. The solvent wasremoved under reduced pressure and the resulting brown solid wasdissolved in dichloromethane (50 ml) and water (50 ml). The organiclayer was separated, washed with water (50 ml), brine (30 ml), driedover magnesium sulphate, filtered and the solvent removed under reducedpressure to give a brown solid. The product was purified by flashchromatography on silica gel eluting with pentane:ethyl acetate (50:50,by volume) to give the title compound as a yellow solid (500 mg), m.p.150-152° C.

¹H NMR (400 MHz, CDCl₃): δ=2.17 (s, 3H), 3.56 (s, 2H), 6.77 (s, 2H),7.02 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 282.

EXAMPLE 2091-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]acetyl}piperidine

Standard solutions: The acid of Preparation 92 (680 mg, 2.16 mmol) and1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(761 mg, 3.23 mmol) were separately dissolved inN,N-dimethylacetamide:triethylamine (96:4) (2×17 ml).

Piperidine (3 mg, 0.031 mmol) was treated with the standard solutions ofthe acid and coupling reagents (250 μl of each) in a 96 well plate andthe mixture was shaken for 14 hours at 80° C. The solvent was removedunder reduced pressure and the mixture dissolved in dimethylsulphoxide(500 μl) and purified by HPLC (Magellen C₁₈(2) 150×10 mm column; agradient mobile phase was used, 5:95 (by volume) to 95:5 (by volume)acetonitrile:(0.1% trifluoroacetic acid in water).

Retention time: 4.7 minutes.

LRMS (electrospray): m/z [MH⁺] 368.

EXAMPLES 210-217

The compounds of the following tabulated Examples of the generalformula:

were performed by a similar method to that of Example 209 using theappropriate amine.

HPLC retention LRMS (electrospray) Example No. X times/min m/z [MH⁺] 210

3.9 384 211

5.5 459 212

5.4 476 213

5.3 458 214

5.1 424 215

5.3 458 216

4.9 408 217

5.2 404

EXAMPLE 2183-chloro-5-[(5-{[(2-chlorobenzyl)amino]methyl}-3-methyl-1H-pyrazol-4-yl)oxy]benzonitrile

Standard solutions: The bromide of Preparation 18 (850 mg, 2.30 mmol)was dissolved in N methylpyrrolidinone (43 ml).

2-Chlorobenzylamine (19 mg, 0.13 mmol) in a 96 well plate was treatedwith the solution of the bromide of Preparation 18 (500 μl) and themixture was shaken for 14 hours at 80° C. The solvent was removed underreduced pressure and the mixture dissolved in dimethylsulphoxide (500μl) and purified by HPLC (Magellen C₈(2) 150×10 mm column; a gradientmobile phase was used, 5:95 (by volume) to 95:5 (by volume)acetonitrile:(0.1% trifluoroacetic acid in water).

Retention time: 5.3 minutes.

LRMS (electrospray): m/z [MH⁺] 386.

EXAMPLES 219-249

The compounds of the following tabulated Examples of the generalformula:

were performed by a similar method to that of Example 218 using theappropriate amine.

HPLC retention LRMS (electrospray) Example No. X times/min m/z [MH⁺] 219

4.2 367 220

4.1 366 221

3.8 374 222

3.2 353 223

4.2 356 224

3.7 334 225

3.7 445 226

4.1 366 227

4.3 387 228

4.2 380 229

3.6 328 230

3.5 347 231

4.3 387 232

4.5 438 233

3.8 353 234

3.7 370 235

4.1 370 236

4.1 396 237

4.1 352 238

4.1 382 239

4.4 420 240

4.0 362 241

4.1 382 242

4.2 372 243

3.2 353 244

4.2 420 245

4.4 421 246

3.7 353 247

4.4 421 248

4.1 382 249

4.1 382

EXAMPLE 2503-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-(methylsulfanyl)benzonitrile

The protected alcohol from Preparation 93 (687 mg, 1.65 mmol) andp-toluene-sulphonic acid (32 mg, 0.17 mmol) were dissolved in methanol(16 ml) and stirred under nitrogen at room temperature. After 4 hours asecond portion of p-toluene-sulphonic acid (32 mg, 0.17 mmol) was added.After 18 hours the solvent was removed under reduced pressure and theresidue was partitioned between saturated aqueous sodium bicarbonatesolution (20 ml) and dichloromethane (20 ml). The aqueous phase wasextracted with dichloromethane (40 ml) and the combined organic extractswere dried over magnesium sulphate, concentrated under reduced pressureand purified by flash chromatography on silica gel eluting withdichloromethane:methanol (97:3, by volume) to provide the title compound(487 mg) as a white solid. m.p. 72° C.

¹H NMR (400 MHz, CDCl₃): δ=1.14 (m, 6H), 2.44 (q, 2H), 2.49 (s, 3H),2.53 (q, 3H), 4.08 (m, 2H), 4.14 (m, 2H), 6.84 (s, 1H), 7.00 (s, 1H),7.10 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 332.

Microanalysis: Found C, 61.36; H, 6.43; N, 12.55. C₁₇H₂₁N₃O₂S requiresC, 61.61; H, 6.39; N, 12.68%.

EXAMPLE 2513-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-(methylsulfinyl)benzonitrile

Wet alumina was prepared by adding water (1 ml) to Brockman grade Ialumina (5 g). To a stirred solution of the sulphide from Example 250(134 mg, 0.40 mmol) in dichloromethane (2 ml) was added of wet alumina(400 mg) followed by Oxone® (123 mg, 0.4 mmol) and the mixture washeated at reflux. After 1 hour a second portion of oxone (123 mg, 0.40mmol) was added and the mixture was heated for a further 2 hours. Aftercooling to room temperature the reaction mixture was filtered and theresulting solids were washed with dichloromethane (20 ml). The filtratewas concentrated and was purified by flash chromatography on silica geleluting with dichloromethane:methanol (a gradient from 99:1 to 90:10, byvolume) to provide the title compound (92 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.12 (m, 6H), 2.44 (q, 2H), 2.53 (q, 2H),2.73 (s, 3H), 4.06 (m, 2H), 4.18 (m, 2H), 7.24 (s, 1H), 7.45 (s, 1H),7.49 (s, 1H).

LRMS (electrospray): m/z [M+Na⁺] 370.

EXAMPLE 2523-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-(methylsulfonyl)benzonitrile

To a stirred solution of the sulphide from Example 250 (133 mg, 0.4mmol) in dichloromethane (2 ml) at −78° C. was added a solution ofmeta-chloroperoxybenzoic acid (138 mg of 50% by weight mixture, 0.4mmol) in dichloromethane (2 ml). The cooling bath was removed and thesolution was stirred at room temperature for 4 hours. The mixture wasquenched by addition of saturated aqueous sodium bicarbonate solution (6ml) and extracted with dichloromethane (3×5 ml). The combined organiccomponents were dried over magnesium sulphate and concentrated. Analysisof the ¹H NMR (400 MHz, CDCl₃) suggested a mixture of the desiredproduct and the sulphoxide from Example 251. The crude product mixturewas dissolved in dichloromethane (2 ml), cooled to −78° C. and to thiswas added meta-chloroperoxybenzoic acid (138 mg of 50% by weightmixture, 0.4 mmol) in dichloromethane (2 ml). The cooling bath wasremoved and the mixture was stirred at room temperature for 1 hour. Themixture was quenched by addition of saturated aqueous sodium bicarbonatesolution (6 ml) and extracted with dichloromethane (3×5 ml). Thecombined organic components were dried over magnesium sulphate andconcentrated. The crude product mixture was purified by flashchromatography on a silica gel eluting with dichloromethane:methanol(98:2, by volume) to provide the title compound contaminated withmeta-chloroperxoybenzoic acid. To a solution of this crude product indichloromethane at −78° C. was added dimethylsulphoxide (30 μl, 0.4mmol). The cooling bath was removed and the mixture was stirred at roomtemperature for 15 minutes. The mixture was quenched by addition of 10%aqueous potassium carbonate solution (10 ml) and the dichloromethane wasevaporated. The remaining aqueous mixture was then extracted withdiethyl ether (2×10 ml) and ethyl acetate (10 ml). The organiccomponents were combined, dried over magnesium sulphate and concentratedto give the crude product mixture which was purified by flashchromatography on a silica gel eluting with dichloromethane:methanol(98:2, by volume) to provide the title compound (26 mg) as a whitesolid. m.p. 133° C.

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.39 (q, 2H), 2.51 (q, 2H),3.06 (s, 3H), 4.05 (m, 2H), 4.10 (m, 2H), 7.39 (s, 1H), 7.67 (s, 1H),7.84 (s, 1H).

LRMS (electrospray): m/z [M+Na⁺] 385.

HRMS: [MH⁺] 364.1329. C₁₈H₂₀N₆O₂ requires 364.1326.

EXAMPLE 2533-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-[2-(dimethylamino)ethoxy]benzonitrile

To a stirred solution of the protected alcohol from Preparation 94 (180mg, 0.39 mmol) in methanol (4 ml) was added para-toluenesulphonic acid(89 mg, 0.47 mmol). After 18 hours at room temperature the solvent wasevaporated under reduced pressure and the residue was partitionedbetween dichloromethane (5 ml) and 10% aqueous potassium carbonatesolution (5 ml). The aqueous phase was separated and extracted with adichloromethane (3 ml). The organic components were combined, dried overmagnesium sulphate and concentrated under reduced pressure. The crudeproduct mixture was purified by flash chromatography on silica geleluting with dichloromethane:methanol (95:5, by volume) followed bydichloromethane:methanol:ammonia (80:20:1, by volume) to provide thetitle compound (63 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.13 (m, 6H), 2.43 (m, 8H), 2.52 (q, 2H),2.85 (m, 2H), 3.81 (broad s, 1H), 4.08 (m, 6H), 6.70 (s, 1H), 6.78 (s,1H), 6.81 (s, 1H).

LRMS (APCI): m/z [MH⁺] 373.

HRMS: [MH⁺] 373.2234. C₂₀H₂₉N₄O₃ requires 373.2234.

EXAMPLES 254-256

The compounds of the following tabulated Examples of the generalformula:

were performed by a similar method to that of Example 253 using asstarting material the appropriate protected alcohol (PA) fromPreparations 95-97.

Example PA prep No. No. R Analytical Data 254 95 CH₂CH₂NHMe ¹H NMR (400MHz, CDCl₃): δ = 1.13 (m, 6H), 2.42 (q, 2H), 2.53 (q, 2H), 2.59 (s, 3H),3.12 (t, 2H), 4.05 (m, 2H), 4.09 (m, 2H), 4.16 (t, 2H), 6.75 (s, 1H),6.81 (s, 1H), 6.82 (s, 1H). LRMS (APCI): m/z [MH⁺] 359 HRMS: [MH⁺]359.2083. C₁₉H₂₇N₄O₃ requires 359.2078. 255 96 CH₂CONH₂ ¹H NMR (400 MHz,CDCl₃): δ = 1.11 (m, 6H), 2.41 (q, 2H), 2.52 (q, 2H), 4.05 (t, 2H), 4.09(t, 2H), 4.46 (s, 2H), 5.74 (broad s, 1H), 6.42 (broad s, 1H), 6.69 (s,1H), 6.85 (s, 2H). LRMS (APCI): m/z 359 (MH⁺) 256 97 CH₂CH₂OCH₃ ¹H NMR(400 MHz, CDCl₃): δ = 1.12 (m, 6H), 2.42 (q, 2H), 2.51 (q, 2H), 3.44 (s,3H), 3.73 (t, 2H), 4.09 (m, 6H), 6.71 (s, 1H), 6.77 (s, 1H), 6.83 (s,1H). LRMS (electrospray): m/z 360 (MH⁺) HRMS: [MH⁺] 360.1920. C₁₉H₂₆N₃O₄requires 360.1918.

EXAMPLE 2573-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-methoxybenzonitrile

The alcohol from Example 202 (87 mg, 0.28 mmol), triphenylphosphine (220mg, 0.84 mmol) and phthalimide (124 mg, 0.84 mmol) were dissolved intetrahydrofuran (5 ml) at 0° C. under nitrogen anddiisopropylazodicarboxylate (165 μl, 0.84 mmol) dissolved intetrahydrofuran (1 ml) was added dropwise. The reaction was allowed towarm to room temperature and was stirred for 18 hours. The solvent wasremoved under reduced pressure, the residue was dissolved in ethanol (6ml) and hydrazine hydrate (68 μl, 1.40 mmol) was added. The slurry wasstirred for 48 hours at room temperature under nitrogen, concentratedunder reduced pressure and the residue was dissolved in methanol. Thesolution was then passed through an SCX column eluting with methanol toremove impurities, then 2M ammonia in methanol solution to elute theproduct. The product was then purified by flash chromatography on silicagel eluting with dichloromethane:methanol (95:5) thendichloromethane:methanol:0.88 ammonia (90:10:1, by volume) to providethe title compound (67 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.13 (m, 6H), 2.19 (broad s, 2H), 2.43 (q,2H), 2.54 (q, 2H), 3.19 (t, 2H), 3.60 (s, 3H), 4.06 (t, 2H), 6.68 (s,1H), 6.73 (s, 1H), 6.80 (s, 1H).

LRMS (electrospray): m/z 315 (MH⁺)

HRMS: [MH⁺] 315.1819. C₁₇H₂₃N₄O₂ requires 315.1816.

EXAMPLE 2583-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-(1H-pyrazol-1-yl)benzonitrile

The alcohol from Example 164 (162 mg, 0.46 mmol), triphenylphosphine(362 mg, 1.38 mmol) and phthalimide (203 mg, 1.38 mmol) were dissolvedin tetrahydrofuran (8 ml) at 0° C. under nitrogen anddiisopropylazodicarboxylate (272 μl, 1.38 mmol) dissolved intetrahydrofuran (1 ml) was added dropwise. The reaction was allowed towarm to room temperature and was stirred for 18 hours. The solvent wasremoved under reduced pressure, the residue was dissolved in ethanol (9ml) and hydrazine hydrate (112 μl, 2.3 mmol) was added. The slurry wasstirred for 48 hours at room temperature under nitrogen, concentratedunder reduced pressure and the residue was dissolved in methanol. Thesolution was then passed through an SCX column eluting with methanol toremove impurities, then 2M ammonia in methanol solution to elute theproduct. The product was then purified by flash chromatography on silicagel eluting with dichloromethane:methanol (95:5) thendichloromethane:methanol:0.880 ammonia (90:10:1, by volume) to providethe title compound (62 mg) as an oil.

¹H NMR (400 MHz, CD₃OD): δ=1.15 (m, 6H), 2.46 (q, 2H), 2.63 (q, 2H),3.13 (t, 2H), 4.13 (t, 2H), 6.54 (s, 1H), 7.17 (s, 1H), 7.69 (s, 1H),7.72 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H).

LRMS (APCI): m/z 351 (MH⁺)

HRMS: [MH⁺] 351.1929. C₁₉H₂₂N₄O₂ requires 351.1928.

EXAMPLE 2593,5-Dichlorophenyl-3-methyl-5-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-pyrazol-4-ylether

To a stirred solution of the acid (100 mg, 0.33 mmol) from Preparation92 in dimethylformamide (2 ml) was added carbonyldiimidazole (59 mg,0.36 mmol) in one portion. After 30 minutes at room temperature(1Z)-N-hydroxyethanimidamide (27 mg, 0.36 mmol) was added and thereaction mixture was stirred at room temperature for 3 hours. A secondportion of carbonyldiimidazole (59 mg, 0.36 mmol) was added and themixture was heated at 100° C. for 12 hours. After cooling to roomtemperature water (30 ml) was added and the mixture was extracted withethyl acetate (3×20 ml). The combined organic components were dried overmagnesium sulphate and concentrated under reduced pressure to give abrown oil. The crude product mixture was purified by flashchromatography on silica gel eluting with ethyl acetate:pentane (30:70,by volume) to provide the title compound (40 mg) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=2.12 (s, 3H), 2.29 (s, 3H), 4.08 (s, 2H),6.74 (s, 2H), 6.98 (s, 1H).

LRMS (electrospray): m/z 339 (MH⁺)

EXAMPLE 2603-Fluoro-5-{[1-(2-hydroxyethyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]oxy}benzonitrile

To a stirred solution of the protected alcohol (85 mg, 0.21 mmol) fromPreparation 99 in methanol (0.5 ml) was added para-toluenesulphonic acid(4 mg, 0.02 mmol). After 5 hours the reaction mixture was concentratedunder reduced pressure, dissolved in dichloromethane (20 ml), washedwith saturated sodium bicarbonate solution (20 ml), dried over magnesiumsulphate and concentrated under reduced pressure. The crude productmixture was purified by flash chromatography on silica gel eluting withpentane:ethyl acetate (60:40 followed by 40:60, by volume) to providethe title compound (54 mg) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ=2.19 (s, 3H), 2.45 (t, 1H), 4.10 (m, 2H),4.20 (m, 2H), 6.87 (d, 1H), 6.96 (s, 1H), 7.05 (d, 1H).

LRMS (APCI): m/z 330 (MH⁺)

Microanalysis: Found C, 51.38; H, 3.52; N, 12.37. C₁₄H₁₁F₄N₃O₂ requiresC, 51.07; H, 3.37; N, 12.76%.

EXAMPLE 2615-[(3,5-Diethyl-1-{2-[(2-methoxymethoxy)methoxy]ethyl}-1H-pyrazol-4-yl)oxy]isophthalonitrile

To a stirred solution of the alcohol (5.0 g, 16.11 mmol) from Example119 in tetrahydrofuran (65 ml) at 0° C. was added2-methoxyethoxymethylchloride (2.39 ml, 20.94 mmol) followed by sodiumhydride (838 mg of a 60% by weight dispersion in oil, 20.94 mmol). After10 minutes the reaction mixture was heated at 50° C. for 18 hours. Aftercooling to room temperature, the mixture was diluted with saturatedaqueous ammonium chloride solution dropwise (3 ml). The mixture wasconcentrated under reduced pressure and the residue was partitionedbetween dichloromethane (250 ml) and water (200 ml). The aqueous phasewas separated and extracted with dichloromethane (150 ml). The organiccomponents were combined, dried over magnesium sulphate and concentratedunder reduced pressure. The crude product mixture was purified by flashchromatography on silica gel eluting with dichloromethane; followed bydichloromethane:methanol (99:1, by volume) to provide the title compound(5.38 g) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.39 (q, 2H), 2.55 (q, 2H),3.38 (s, 3H), 3.51 (m, 2H), 3.56 (m, 2H), 3.93 (t, 2H), 4.20 (t, 2H),4.66 (s, 2H), 7.38 (s, 2H), 7.56 (s, 1H).

LRMS (APCI): m/z 399 (MH⁺)

Microanalysis: Found C, 62.11; H, 6.67; N, 13.51. C₂₁H₂₆N₄O₄+0.43H₂Orequires C, 62.09; H, 6.67; N, 13.79%.

EXAMPLE 2623-Cyano-5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}benzamide

To a stirred solution of the pyrazole (60 mg) from Preparation 100 indichloromethane (4 ml) was added aluminium trichloride (134 mg, 1 mmol).After 18 hours, ice was added, the mixture was neutralised usingsaturated aqueous sodium bicarbonate solution, diluted with water (30ml) and extracted with dichloromethane (2×40 ml). The organic componentswere combined, dried over magnesium sulphate and concentrated underreduced pressure. The crude product mixture was purified by flashchromatography on silica gel eluting with dichloromethane:methanol(95:5, by volume) to provide the title compound (27 mg) as a colourlessglass.

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.40 (q, 2H), 2.52 (q, 2H),4.07 (m, 4H), 7.25 (s, 1H), 7.60 (s, 1H), 7.65 (s, 1H).

LRMS (APCI): m/z 329 (MH⁺)

EXAMPLE 2635-{[5-Ethyl-3-(1-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile

To a stirred solution of the pyrazole from Preparation 102 (219 mg, 0.57mmol) in tetrahydrofuran (2.5 ml) was added saturated aqueous sodiumcarbonate solution (0.5 ml). The reaction mixture was stirred at roomtemperature for 4 hours and then heated at reflux for 18 hours. Thereaction mixture was concentrated under reduced pressure and the residuewas partitioned between dichloromethane (20 ml) and water (20 ml). Theorganic phase was dried over magnesium sulphate and concentrated underreduced pressure. The crude product mixture was purified by flashchromatography on silica gel eluting with dichloromethane:methanol (agradient from 100:0 to 90:10, by volume) to provide the title compound(68 mg) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ=1.21 (t, 3H), 1.51 (d, 3H), 2.54 (q, 2H),4.89 (q, 1H), 7.25 (s, 2H), 7.43 (s, 1H).

LRMS (APCI): m/z 283 (MH⁺)

EXAMPLE 2645-{[5-Ethyl-3-(1-hydroxyethyl)-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile

To a stirred solution of the pyrazole from Preparation 103 (80 mg, 0.19mmol) in methanol (1 ml) was added para-toluenesulphonic acid (4 mg,0.02 mmol). After 5 hours at room temperature the reaction mixture wasconcentrated under reduced pressure and the residue was partitionedbetween dichloromethane (20 ml) and water (20 ml). The organic componentwas dried over magnesium sulphate and concentrated under reducedpressure. The crude product mixture was purified by flash chromatographyon silica gel eluting with dichloromethane:methanol (a gradient from100:0 to 95:5, by volume) to provide the title compound (44 mg) whitesolid.

¹H NMR (400 MHz, CDCl₃): δ=1.11 (t, 3H), 1.46 (d, 3H), 2.54 (q, 2H),4.10 (q, 2H), 4.17 (q, 2H), 4.79 (q, 1H), 7.44 (s, 2H), 7.57 (s, 1H).

LRMS (APCI): m/z 327 (MH⁺)

EXAMPLE 2653-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)benzonitrile

To a stirred solution of the pyrazole from Preparation 105 (235 mg, 0.46mmol) in dichloromethane (2 ml) was added aluminium trichloride (373 mg,2.8 mmol). The reaction mixture was stirred at room temperature for 48hours, diluted with water (6 ml) and extracted with dichloromethane (6ml). The organic component was concentrated under reduced pressure andpurified by flash chromatography on silica gel eluting withdichloromethane:methanol (a gradient from 99:1 to 80:20, by volume)followed by dichloromethane:methanol:0.88 ammonia (80:20:1, by volume)to provide an impure sample of the title compound (44 mg) as a whitesolid. The product was further purified by HPLC using a Phenomonex LunaC₁₈ 150×21.2 mm column eluting with a solvent gradient of 5:95 0.1%aqueous trifluoroacetic acid in acetonitrile:acetoritrile (0-1 min80:20; 1-7 min 80:20 changing to 0:100; 7-12 min 0:100; 12-12.1 min0:100 changing to 80:20; 12.1-15 min 80:20) to provide the titlecompound (38 mg) as a white solid.

Retention time 5.7 minutes.

LRMS (electrospray): m/z 422 (MH⁺)

EXAMPLES 266-268

The compounds of the following tabulated Examples of the generalformula:

were prepared by a similar method to that of Example 265 using theappropriate protected alcohol (PA) from Preparation 106-108.

Example No. PA prep No. R Analytical Data 266 106 Me Retention time 4.8minutes LRMS (electrospray): m/z [MH⁺] 368 267 107 Et Retention time 5.3minutes LRMS (electrospray): m/z [MH⁺] 382 268 108 ^(i)Pr Retention time5.7 minutes LRMS (electrospray): m/z 396 (MH⁺)

EXAMPLE 2695-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}amino)methyl]nicotinamide

To a stirred solution of the amine from Preparation 111 (650 mg, 1.70mmol) in iso-propyl alcohol (6 ml) was added the pyrazole fromPreparation 18 (210 mg, 0.57 mmol) followed by potassium carbonate (240mg, 1.70 mmol). The reaction mixture was heated at reflux for 1.5 hours.After cooling to room temperature the mixture was concentrated underreduced pressure and the crude product mixture was purified by flashchromatography on silica gel eluting with dichloromethane:methanol:0.88ammonia (95:5:0.5 then 90:10:1 then 80:20:1, by volume) which gave animpure sample of the desired product. Flash chromatography was repeatedeluting with dichloromethane:methanol:0.88 ammonia (100:0:0 then95:5:0.5 then 90:10:1, by volume) to provide the title compound (10 mg)as a pale yellow solid.

¹H NMR (400 MHz, CD₃OD): δ=2.05 (s, 3H), 3.62 (s, 2H), 3.79 (s, 2H),7.16 (m, 1H), 7.18 (m, 1H), 7.38 (s, 1H), 8.15 (s, 1H), 8.54 (s, 1H),8.84 (s, 1H).

LRMS (APCI): m/z 419 (M+Na⁺)

HRMS: [MH⁺] 397.1173. C₁₉H₁₈N₆O₂Cl requires 397.1175.

EXAMPLE 2702-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}amino)methyl]isonicotinamide

To a stirred suspension of the amine from Preparation 115 (250 mg, 1.66mmol) and the pyrazole from Preparation 18 (155 mg, 0.42 mmol) inisopropanol (6 ml) was added tetrahydrofuran (2 ml). The mixture washeated at reflux for 2 hours after which the reaction mixture wasconcentrated under reduced pressure. The crude product mixture waspurified by flash chromatography on silica gel eluting withdichloromethane:methanol:0.88 ammonia (85:15:1, by volume) to provide animpure sample of the title compound. The product was further purified byHPLC using a Phenomonex Luna C₈(II) 10 μM 150×21.2 mm column elutingwith a solvent gradient of 5:95 0.1% aqueous trifluoroacetic acid inacetonitrile:acetonitrile (0-6 min 95:5 changing to 0:100; 6-10 min0:100) to provide the title compound (65 mg) as an off-white solid.

Retention time: 3.40 minutes

¹H NMR (400 MHz, CD₃OD): δ=2.14 (s, 3H), 4.21 (s, 2H), 4.50 (s, 2H),7.19 (s, 1H), 7.27 (m, 1H), 7.43 (m, 1H), 7.48 (m, 1H), 7.78 (m, 1H),8.68 (d, 1H)

LRMS (electrospray): m/z 397 (MH⁺)

Microanalysis: Found C, 44.56; H, 3.41; N, 14.07.C₁₉H₁₇N₆O₂Cl+1.9CF₃CO₂H requires C, 44.64; H, 3.11; N, 13.70%.

EXAMPLE 271 Di(tert-butyl)2-[4-(3,5-dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl phosphate

To a stirred solution of the alcohol from Example 119 (500 mg, 1.60mmol) in dichloromethane (5 ml) was added tetrazole (226 mg, 3.20 mmol)followed by di-tert-butyl-N,N-diisopropylphosphoramidite (1.02 ml, 3.20mmol). After stirring for 4 hours at room temperature the reactionmixture was cooled to 0° C. and meta-chloroperoxybenzoic acid (1.0 g of50% by weight mixture, 3 mmol) was added portionwise (CARE, EXOTHERM).After 10 minutes the mixture was warmed to room temperature and wasdiluted with dichloromethane (50 ml). The solution was washed withsaturated aqueous sodium carbonate solution (20 ml) and the aqueouscomponent was separated and extracted with dichloromethane (20 ml). Thecombined organic components were washed with brine (20 ml), dried overmagnesium sulphate and concentrated under reduced pressure. The crudeproduct mixture was purified by flash chromatography on silica geleluting with dichloromethane:methanol:0.88 ammonia (100:0:0 then99:1:0.1 then 98:2:0.2, by volume) to provide a sample of the titlecompound (660 mg)

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 1.43 (s, 18H), 2.38 (q, 2H),2.55 (q, 2H), 4.26 (m, 4H), 7.38 (s, 2H), 7.54 (s, 1H).

LRMS (electrospray): m/z 525 (MH⁺)

Microanalysis: Found C, 57.77; H, 7.38; N, 10.33. C₂₅H₃₅N₄O₅P+H₂Orequires C, 57.68; H, 7.16; N, 10.76%.

EXAMPLE 272 2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyldihydrogen phosphate

To a stirred solution of the phosphate ester from Example 271 (250 mg,0.48 mmol) in dichloromethane (10 ml) at 0° C. was added trifluoroaceticacid (0.5 ml). The reaction mixture was allowed to warm to roomtemperature and after 4 hours it was concentrated under reducedpressure. The residue was purified by HPLC using a Phenomonex LunaC₈(II) 10 μM 150×21.2 mm column eluting with a solvent gradient of 5:950.1% aqueous trifluoroacetic acid in acetonitrile:acetonitrile (0-1.9min 95:5; 2-10 min 90:10 changing to 30:70; 10.0-13.8 min 30:70;13.8-13.9 min 30:70 changing to 95:5; 13.9-15 min 95:5) to give a sampleof the desired product. This sample was further purified byrecrystallisation using acetonitrile/water which gave the title compoundas a white solid, m.p. 198-199° C.

Retention time: 2.31 minutes.

¹H NMR (400 MHz, CD₃OD): δ=1.09 (m, 6H), 2.35 (q, 2H), 2.61 (q, 2H),4.28 (m, 4H), 7.55 (s, 2H), 7.79 (s, 1H).

LRMS (APCI): m/z 391 (MH⁺)

Microanalysis: Found C, 50.99; H, 4.92; N, 14.06. C₁₇H₁₉N₄O₅P+0.5H₂Orequires C, 51.13; H, 5.05; N, 14.03%.

EXAMPLE 2735-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrilesulfate salt

To a stirred solution of the pyrazole from Example 119 (200 mg, 0.65mmol) in acetone (5 ml) was added sulfuric acid (0.32 ml of a 2M aqueoussolution, 0.64 mmol) and the mixture was stirred at room temperature andthe solvent allowed to evaporate. The residue was recrystallised(toluene/acetone) to give the title compound (160 mg) as a white powder,m.p. 105-110° C.

¹H NMR (400 MHz, CDCl₃): δ=1.22 (m, 6H), 2.70 (m, 4H), 4.12 (bs, 1H),4.59 (m, 2H), 4.75 (bs, 1H), 7.66 (s, 1H), 7.69 (m, 1H), 7.72 (s, 1H).

Microanalysis: Found C, 50.29; H, 4.90; N, 13.48. C₁₇H₁₈N₄O₂.H₂SO₄requires C, 49.99; H, 4.93; N, 13.72%.

EXAMPLE 2745-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrilebenzenesulfonic acid salt

To a stirred solution of the pyrazole from Example 119 (20 g, 65 mmol)in acetone (200 ml) was added benzenesulfonic acid (10.7 g, 68 mmol) andthe mixture was stirred at room temperature for 10 minutes. The reactionmixture was concentrated under reduced pressure and the residue wasrecrystallised twice (acetone) to give the title compound (16.2 g) as awhite powder, m.p. 142-144° C.

¹H NMR (400 MHz, CDCl₃): δ=1.05-1.08 (m, 6H), 2.59 (q, 2H), 2.68 (q,2H), 4.04 (t, 2H), 4.54 (t, 2H), 7.35-7.42 (m, 3H), 7.55 (s, 1H), 7.64(s, 1H), 7.86 (d, 2H).

Microanalysis: Found C, 58.86; H, 5.13; N, 11.88. C₂₃H₂₄N₄O₅S requiresC, 58.96; H, 5.16; N, 11.96%.

EXAMPLE 2755-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitriletosylate salt

To a stirred suspension of the pyrazole from Example 119 (300 mg, 1.00mmol) in ethanol (2 ml) was added p-toluenesulfonic acid (202 mg, 1.10mmol) and the mixture was heated on an oil bath until the solidsdissolved. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was crystallised(diethyl ether), filtered and recrystallised (isopropyl alcohol) to givethe title compound (200 mg) as a white solid, m.p. 120° C.

¹H NMR (400 MHz, DMSO-d₆): δ=1.00 (m, 6H), 2.24 (m, 5H), 2.49 (m, 2H),4.00 (m, 2H), 7.11 (d, 2H), 7.45 (d, 2H), 7.73 (s, 2H), 8.09 (s, 1H).

Microanalysis: Found C, 59.64; H, 5.46; N, 11.60. C₂₄H₂₆N₄O₅S requiresC, 59.74; H, 5.43; N, 11.61%.

EXAMPLE 2765-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrilemesylate salt

To a stirred suspension of the pyrazole from Example 119 (250 mg, 0.83mmol) in isopropyl alcohol (3 ml) was added methanesulfonic acid (52 μl,0.91 mmol) and the mixture was heated on an oil bath until the solidsdissolved. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to a volume of 1 ml. A white solidprecipitated out which was washed with cold isopropyl alcohol to givethe title compound (239 mg) as a white solid, m.p. 144-146° C.

¹H NMR (400 MHz, DMSO-d₆): δ=1.02 (m, 6H), 2.32 (q, 2H), 2.43 (s, 3H),2.52 (m, 2H), 3.73 (m, 2H), 4.02 (m, 2H), 7.75 (s, 2H), 8.11 (s, 1H).

Microanalysis: Found C, 53.20; H, 5.52; N, 13.68. C₁₈H₂₂N₄O₅s requiresC, 53.19; H, 5.46; N, 13.78%.

EXAMPLE 2773-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrilebis-mesylate salt

To a stirred solution of the amine from Example 125 (119 mg, 0.40 mmol)in ethanol (2 ml) was added methanesulfonic acid (1.00 ml of a 0.84Msolution in ethanol, 0.84 mmol). The reaction mixture was concentratedunder reduced pressure to remove some of the ethanol. A mixture ofdiethyl ether and acetone were added and a white solid precipitated outwhich was filtered and washed (diethyl ether/acetone) to give the titlecompound (153 mg) as a white solid, m.p. 146-148° C.

¹H NMR (400 MHz, CD₃OD): δ=1.09 (m, 6H), 2.33 (s, 3H), 2.39 (q, 2H),2.55 (q, 2H), 2.68 (s, 6H), 3.42 (t, 2H), 4.29 (t, 2H), 6.93 (s, 1H),7.06 (s, 1H), 7.19 (s, 1H).

LRMS (thermospray): m/z [free base+H⁺] 299

Microanalysis: Found C, 45.83; H, 6.12; N, 11.27. C₁₉H₃₀N₄O₇S₂.0.50H₂Orequires C, 45.68; H, 6.25; N, 11.21%.

EXAMPLE 2783-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrilephosphate salt

To a stirred solution of the amine from Example 125 (251 mg, 0.84 mmol)in ethanol (5 ml) was added phosphoric acid (63 μl, 0.93 mmol). Theresulting precipitate was filtered, washed (ethanol then diethyl ether)and dried to give the title compound (265 mg) as a white solid, m.p.210-211° C.

¹H NMR (400 MHz, CD₃OD): δ=1.08 (m, 6H), 2.32 (s, 3H), 2.39 (q, 2H),2.56 (q, 2H), 3.39 (m, 2H), 4.29 (m, 2H), 6.93 (s, 1H), 7.05 (s, 1H),7.18 (s, 1H).

LRMS (thermospray): m/z [free base+H⁺] 299

Microanalysis: Found C, 51.26; H, 6.36; N, 14.08. C₁₇H₂₅N₄O₅P requiresC, 51.51; H, 6.36; N, 14.14%.

EXAMPLE 2793-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrile(L) tartrate salt

To a stirred solution of the amine from Example 125 (500 mg, 1.68 mmol)in acetone (15 ml) was added (L)-tartaric acid (252 mg, 1.68 mmol) andthe mixture was heated on an oil bath until complete dissolution hadoccurred. The mixture was cooled to room temperature and a whiteprecipitate formed which was filtered and washed (acetone) to give thetitle compound (515 mg) as a white powder, m.p. 159-161° C.

¹H NMR (400 MHz, CD₃OD): δ=1.05-1.10 (m, 6H), 2.32 (s, 3H), 2.34-2.41(m, 2H), 2.53-2.57 (m, 2H), 3.40 (m, 2H), 4.27 (m, 2H), 4.35 (s, 2H),6.93 (s, 1H), 7.05 (s, 1H), 7.17 (s, 1H).

LRMS (electrospray): m/z [free base+H⁺] 299

Microanalysis: Found C, 54.80; H, 6.38; N, 12.11. C₂₁H₂₈N₄O₇.0.65H₂Orequires C, 54.81; H, 6.42; N, 12.10%.

EXAMPLE 2803-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrilesuccinate salt

To a stirred solution of the amine from Example 125 (235 mg, 0.79 mmol)in acetone (7 ml) was added succinic acid (93 mg, 0.79 mmol). After twominutes the mixture was concentrated to −3 ml using a stream of nitrogengas which resulted in the formation of white crystals. The precipitatewas filtered and washed (acetone) to give the title compound (172 mg) aswhite crystals, m.p. 155° C.

¹H NMR (400 MHz, CD₃OD): δ=1.03-1.07 (m, 6H), 2.34 (s, 3H), 2.40 (q,2H), 2.50 (s, 4H), 2.59 (q, 2H), 3.34 (t, 2H), 4.23 (t, 2H), 6.95 (s,1H), 7.06 (s, 1H), 7.22 (s, 1H).

LRMS (electrospray): m/z [free base+H⁺] 299

Microanalysis: Found C, 60.47; H, 6.77; N, 13.39. C₂₁H₂₈N₄O₅ requires C,60.56; H, 6.78; N, 13.45%.

EXAMPLE 2813-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrile(L) citrate salt

To a stirred solution of the amine from Example 125 (140 mg, 0.47 mmol)in acetone (3 ml) was added citric acid (90 mg, 0.47 mmol). The mixturewas stirred until complete dissolution had occurred. The mixture wasconcentrated to −1 ml using a stream of nitrogen gas and cooled in afreezer for 1.5 hours. A precipitate collected which was filtered togive the title compound (149 mg) as a white powder, m.p. 180-182° C.

¹H NMR (400 MHz, CD₃OD): δ=1.04-1.07 (m, 6H), 2.35 (s, 3H), 2.40 (q,2H), 2.58 (q, 2H), 2.73 (d, 2H), 2.80 (d, 2H), 3.42 (t, 2H), 4.30 (t,2H), 6.95 (s, 1H), 7.08 (s, 1H), 7.21 (s, 1H).

LRMS (electrospray): m/z [free base+H⁺] 299

Microanalysis: Found C, 56.19; H, 6.20; N, 11.31. C₂₃H₃₀N₄O₈ requires C,56.32; H, 6.16; N, 11.42%.

EXAMPLE 2825-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile

2-Hydroxyethylhydrazine (8.43 ml, 124 mmol) was added dropwise to asolution of the diketone of Preparation 45 (30.5 g, 113 mmol) in aceticacid (300 ml) at room temperature under nitrogen. The reaction wasstirred at room temperature for 90 minutes and the solvent removed underreduced pressure to give an orange solid. This was combined with anorange solid from another reaction carried out in an identical manner tothis. The combined crude product was purified by flash columnchromatography on silica gel eluting with ethyl acetate:pentane (75:25by volume) to provide the title compound as a white solid. Analysis ofthe proton nmr showed minor impurities were present so the product waspurified by flash column chromatography on silica gel eluting with ethylacetate:pentane (50:50 by volume) to provide the title compound (50 g)as a white solid, m.p. 125° C.

¹H-NMR (400 MHz, CDCl₃): δ=1.13 (6H, m), 2.40 (2H, q), 2.53 (2H, q),3.53 (1H, m), 4.11 (4H, m), 7.40 (2H, s), 7.58 (1H, s).

LRMS (electrospray): m/z [MH⁺] 311.

Microanalysis: Found: C, 65.62; H, 5.85; N, 18.04. C₁₇H₁₈N₄O₂ requiresC, 65.64; H, 5.84; N, 18.05%.

EXAMPLE 2832-[4-(3,5-Dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl]ethylamine and2-[4-(3,5-Dichlorophenoxy)-5-ethyl-1H-pyrazol-1-yl]ethylamine

The pyrazole from Example 42 (1.039, 4.00 mmol) and 2-chloroethylaminehydrochloride (510 mg, 4.40 mmol) were heated as a melt at 150° C. for24 hours. The reaction was cooled and a solution of the residue indichloromethane (100 ml) was washed with an aqueous solution of 1Mpotassium carbonate (50 ml), brine (50 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography on silica gel eluting withdichloromethane:methanol:ammonia (93:7:1, by volume) to afford the titlecompounds (768 mg) in a 85:15 ratio of regioisomers as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.16 (major, t, 3H), 1.16 (minor, t, 3H),2.47 (major, q, 2H), 2.60 (minor, q, 2H), 3.13 (major, m, 2H). 3.13(minor, m, 2H), 4.10 (major, m, 2H), 4.10 (minor, m, 2H), 4.24 (major,t, 2H), 4.24 (minor, t, 2H), 6.85 (major, s, 2H), 6.85 (minor, s, 2H),7.02 (major, s, 1H), 7.02 (minor, s, 1H), 7.27 (major, s, 1H), 7.31(minor, s, 1H).

LRMS (thermospray): m/z [MH⁺] 300.

The following Preparations describe the preparation of certainintermediates used in the preceding Examples.

Preparation 1 3-(3,5-Dichlorophenoxy)-2,4-pentanedione

3-Chloro-2,4-pentanedione (183 μL, 1.53 mmol)) was added to a stirredsuspension of 3,5-dichlorophenol (250 mg, 1.53 mmol) and potassiumcarbonate (233 mg, 1.69 mmol) in acetone (7.7 ml) at room temperatureunder nitrogen. The mixture was stirred for 30 minutes and then heatedunder reflux for 3½ hours. After cooling, sodium iodide (230 mg, 1.53mmol) was added and refluxing continued for a further 3½ hours. Aftercooling again the mixture was diluted with water (5 ml) and concentratedunder reduced pressure in a fumehood (Caution: possible residuallachrymator) to remove acetone. The resulting red aqueous solution wasdiluted with 2M hydrochloric acid (5 ml) and extracted withdichloromethane (3×10 ml). The combined organic layers were washed withsaturated aqueous sodium sulphite solution (10 ml) and brine (10 ml),dried over magnesium sulphate, filtered and evaporated under reducedpressure to leave a red oil (344 mg). The crude product was purified byflash chromatography on silica gel eluting with pentane:ethyl acetate(20:1, by volume) to give the title compound (118 mg) as a cream solidm.p. 91-92° C.

¹H-NMR (400 MHz, CDCl₃): δ=2.04 (s, 6H), 6.84 (s, 2H), 7.06 (s, 1H),14.38 (br.s, 1H)

LRMS (thermospray): m/z [MNH₄ ⁺] 278.

Microanalysis: Found: C, 50.43; H, 3.84. C₁₁H₁₀Cl₂O₃ requires C, 50.60;H, 3.86%.

Preparation 2 4-Chloro-3,5-heptanedione

Chlorotrimethylsilane (29.7 ml, 0.234 mol) was added dropwise to astirred pale yellow solution of tetrabutylammonium bromide (1.26 g, 3.9mmol) in dry acetonitrile (16 ml) at room temperature under nitrogen.The resulting solution was cooled in ice and 3,5-heptanedione (10.6 ml,78.0 mmol) and then dry dimethylsulphoxide (16.6 ml, 0.234 mol) wereadded dropwise over 5 minutes producing a yellow solution which wasallowed to warm slowly to room temperature, with stirring, over 4 hours.The mixture was diluted with water (litre), stirred for 10 min and thenextracted with ether (1×500 ml, 2×250 ml). The combined ether layerswere dried over magnesium sulphate, filtered and concentrated underreduced pressure to leave a yellow oil. The crude product was purifiedby distillation under reduced pressure to afford the title compound (5.5g) as a pale yellow oil, b.p. 102-105° C./54 mmHg containing ca. 10%4,4-dichloro-3,5-heptanedione as estimated by microanalysis.

¹H-NMR (400 MHz, CDCl₃): δ=1.12 (t, 6H), 2.59 (q, 4H), 4.77 (s, 0.2H,diketone), 15.50 (s, 0.8H, enol).

LRMS (thermospray): m/z [MNH₄ ⁺] 180 for title compound and 214 fordichlorinated impurity.

Preparation 3 Ethyl4-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-3-oxobutanoate

Sodium hydride (60% dispersion in oil, 250 mg, 6.17 mmol) was added to astirred solution of 4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole (800mg, 2.81 mmol, Example 3) in dry N,N-dimethylformamide (5 ml) at 0° C.under nitrogen. The mixture was stirred for 5 minutes during which timehydrogen was evolved and then ethyl 4-chloroacetoacetate (0.42 ml, 3.09mmol) was added. After 30 minutes the reaction mixture was quenched bythe addition of water (0.5 ml) and concentrated under reduced pressure.A solution of the residue in ethyl acetate (50 ml) was washed withsaturated aqueous ammonium chloride solution (20 ml) and water (20 ml),dried over magnesium sulphate and concentrated under reduced pressure.The crude product was purified by flash chromatography on silica geleluting with ethyl acetate:pentane (30:70, by volume) to provide thetitle compound (1.1 g) as a white solid, m.p. 82-84° C.

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (6H, m), 1.26 (3H, t), 2.44 (4H, q),3.47 (2H, s), 4.22 (2H, q), 4.96 (2H, s), 6.82 (2H, s), 7.02 (1H, s).

LRMS (thermospray): m/z [MH⁺] 413.

Microanalysis: Found: C, 55.13; H, 5.34; N, 6.98. C₁₅H₁₅Cl₂N₃O requiresC, 55.22; H, 5.37; N, 6.78%.

Preparation 4[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetic acid

Aqueous sodium hydroxide solution (1N, 6.2 ml, 6.2 mmol) was addeddropwise to a stirred solution of the ester (2 g, 5.6 mmol) of Example 9in tetrahydrofuran (20 ml) at 0° C. After 1 hour the solvent was removedunder reduced pressure and aqueous hydrochloric acid (20 ml) was addedwith vigorous stirring. The resulting white precipitate was collected byfiltration, washed with ether (3×30 ml) and dried in a vacuum pistol at60° C./10 mmHg to afford the title compound as a white solid (1.5 g),m.p. 157-158° C.

¹H-NMR (300 MHz, CDCl₃): δ=1.13 (6H, m), 2.52 (2H, q), 2.60 (2H, q),5.03 (2H, s), 6.95 (2H, s), 7.14 (1H, s).

LRMS (electrospray): m/z [M-H⁺] 341.

Preparation 5 1-(3,5-Dichlorophenoxy)-2-butanone

Cesium carbonate (108 g, 0.33 mol) was added in one portion to a stirredsolution of 3,5-dichlorophenol (49 g, 0.30 mol) in acetone (900 ml) atroom temperature under nitrogen. To this suspension a solution of1-bromo-2-butanone (30.6 ml, 0.30 mol) in acetone (300 ml) was addeddropwise and the resultant suspension was heated under reflux for 2hours. The suspension was cooled to room temperature, water (200 ml) wasadded and the acetone was removed under reduced pressure. The mixturewas extracted with dichloromethane (2×300 ml) and the combined organicphases were dried over magnesium sulphate, filtered and concentratedunder reduced pressure to leave a clear oil. The crude product waspurified by flash column chromatography on silica gel eluting withdichloromethane:cyclohexane (50:50, by volume) to provide the titlecompound (65 g) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.13 (t, 3H), 2.60 (q, 2H), 4.58 (s, 2H),6.78 (s, 2H), 7.01 (s, 1H).

LRMS (thermospray): m/z [MNH₄ ⁺] 250.

Preparation 6 2-(3,5-Dichlorophenoxy)-1-(dimethylamino)-1-penten-3-one

A solution of the ketone of Preparation 5 (65 g, 0.28 mol) inN,N-dimethylformamide dimethylacetal (75 ml, 0.56 mol) was heated at100° C. using a Dean-Stark apparatus for 10 hours. The reaction wascooled and concentrated under reduced pressure to leave a brown oil. Thecrude product was purified by flash column chromatography on silica geleluting with pentane:ethyl acetate (90:10, by volume) and thenpentane:ethyl acetate (60:40, by volume) to provide the title compound(55 g) as a yellow oil that solidified upon standing. The resultantyellow solid was washed with pentane (100 ml) and dried to provide thetitle compound (28 g) as a yellow solid, m.p. 96-97° C.

¹H-NMR (400 MHz, CDCl₃): δ=0.98 (t, 3H), 2.30 (br s, 2H), 2.94 (s, 6H),6.77 (s, 2H), 6.95 (s, 1H), 7.24 (s, 1H).

LRMS (thermospray): m/z [MNH₄ ⁺] 288.

Preparation 7 1-Acetyl-4-(3,5-dichlorophenoxy)-3,5-dimethyl-1H-pyrazole

Sodium hydride (60% dispersion in oil, 684 mg, 17.1 mmol) was added to astirred solution of acetyl chloride (1.21 ml, 17.1 mmol) and thepyrazole of Example 53 (4.00 g, 15.6 mmol) in N,N-dimethylformamide (20ml) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 1hour and then quenched by the addition of water (100 ml). The aqueousextracted was with ether (2×50 ml). The combined organic phases werewashed with water (30 ml) and brine (30 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure to leave ayellow solid. The crude product was purified by flash columnchromatography on silica gel eluting with pentane:ether (90:10, byvolume) to provide the title compound (3.0 g) as a white solid, m.p.<60°C.

¹H-NMR (300 MHz, CDCl₃): δ=2.11 (s, 3H), 2.43 (s, 3H), 2.70 (s, 3H),6.78 (s, 2H), 7.03 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 299.

Preparation 81-Acetyl-3-(bromomethyl)-4-(3,5-dichlorophenoxy)-5-methyl-1H-pyrazole

N-Bromosuccinimide (2.70 g, 15.0 mmol) was added to a stirred solutionof the pyrazole of Preparation 7 (3.00 g, 10.0 mmol) in1,1,1-trichloroethane (40 ml) at room temperature under nitrogen. Thereaction was heated at 80° C. for 1 hour and then azobisisobutyronitrile(2 mg) was added and the reaction mixture was heated for a further 3hours. The reaction was cooled to room temperature and a solid removedby filtration. The filtrate was concentrated under reduced pressure andthe resulting yellow oil was dissolved in ethyl acetate (100 ml). Theethyl acetate was washed with 1M aqueous sodium carbonate solution (30ml), water (30 ml) and brine (30 ml), dried over magnesium sulphate,filtered and concentrated under reduced pressure to leave a yellowsolid. The crude product was purified by flash column chromatography onsilica gel eluting with pentane:ethyl acetate (90:10, by volume) toprovide a yellow solid that was washed with ice cold ether (20 ml) toprovide the title compound (2.3 g) as a white solid, m.p. 111-113° C.

¹H-NMR (300 MHz, CDCl₃): δ=2.10 (s, 3H), 2.73 (s, 3H), 4.73 (s, 2H),6.86 (s, 2H), 7.11 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 379.

Preparation 9 4-(3-Cyanophenoxy)-3,5-heptanedione

A mixture of the β-diketone of Preparation 2 (1.79 g, 11.0 mmol),3-cyanophenol (1.31 g, 11.0 mmol), cesium carbonate (3.58 g, 11.0 mmol)and acetone (44 ml) was heated under reflux for 2 hours. After cooling,the mixture was concentrated under reduced pressure and the residue waspartitioned between dichloromethane (50 ml) and water (25 ml). Theorganic layer was separated, washed with brine (25 ml), dried overmagnesium sulphate, filtered and concentrated under reduced pressure toleave a yellow oil. The crude product was purified by flash columnchromatography on silica gel eluting with ethyl acetate:pentane (10:90,by volume) to provide the title compound (1.10 g) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.04 (t, 6H), 2.49 (q, 4H), 7.16 (m, 2H),7.30 (d, 1H), 7.39 (t, 2H), 14.51 (s, 1H).

LRMS (thermospray): m/z [MNH₄ ⁺] 263.

Preparation 10 tert-Butyl 3-(hydroxymethyl)-4-morpholinecarboxylate

Borane (38.1 ml of a 1.0M solution in tetrahydrofuran, 38.1 mmol) wasadded dropwise to a stirred suspension of 3-morpholinecarboxylic acid(1.00 g, 7.63 mmol) in tetrahydrofuran (50 ml) at room temperature undernitrogen. The reaction was heated under reflux and the reaction becamehomogeneous and heating was continued for 12 hours. The reaction wascooled to room temperature and concentrated under reduced pressure toleave a brown oil. The residue was dissolved in 1M aqueous sodiumhydroxide solution and stirred at room temperature for 5 days. Afterthis time di-tert-butyl dicarbonate (1.66 g, 7.63 mmol) was added andthe reaction was stirred for 12 hours. The reaction was diluted withether (100 ml). The organic layer was separated, washed with brine (10ml), dried over magnesium sulphate, filtered and concentrated underreduced pressure. The crude product was purified by flash columnchromatography on silica gel eluting with pentane:ethyl acetate (50:50,by volume) and then ethyl acetate to provide the title compound (1.30 g)as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.48 (s, 9H), 2.05 (s, 1H), 3.19 (br t, 1H),3.47 (td, 1H), 3.60 (dd, 1H), 3.87 (m, 6H).

LRMS (thermospray): m/z [MH⁺] 218.

Preparation 11 tert-Butyl3-{[(methylsulfonyl)oxy]methyl}-4-morpholinecarboxylate

Triethylamine (1.15 ml, 8.29 mmol) was added dropwise to a stirredsolution of the alcohol of Preparation 10 (1.20 g, 5.52 mmol) andmethanesulfonic anhydride (1.449, 5.52 mmol) in dichloromethane (50 ml)at room temperature under nitrogen. The reaction was stirred for 1 hourand then poured onto water (50 ml). The organic layer was separated,dried over magnesium sulphate, filtered and concentrated under reducedpressure. The crude product was purified by flash column chromatographyon silica gel eluting with pentane:ethyl acetate (50:50, by volume) toprovide the title compound (1.20 g) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.49 (s, 9H), 3.06 (s, 3H), 3.50 (td, 1H),3.60 (dd, 1H), 3.80 (m, 4H), 4.26 (br s, 1H), 4.39 (m, 2H).

LRMS (thermospray): m/z [MNH₄ ⁺] 313.

Preparation 12 Methyl-2-(3,5-dichlorophenoxy)-3-oxopentanoate

A mixture of methyl-2-chloro-3-pentanoate (25.0 g, 152 mmol),3,5-dichlorophenol (24.6 g, 152 mmol), cesium carbonate (54.4 g, 167mmol) and acetone (500 ml) was heated under reflux for 2 hours. Aftercooling the mixture was concentrated under reduced pressure and theresidue was partitioned between dichloromethane (100 ml) and water (50ml). The organic layer was separated, washed with brine (25 ml), driedover magnesium sulphate, filtered and concentrated under reducedpressure to leave an orange oil. The crude product was purified by flashcolumn chromatography on silica gel eluting with pentane:toluene (90:10,by volume) to provide the title compound (40.0 g) as a pink oil.

¹H-NMR (300 MHz, CDCl₃): δ=1.16 (t, 3H), 2.60 (m, 2H), 3.77 (s, 3H),5.13 (s, 1H), 6.84 (s, 2H), 7.10 (s, 1H).

LRMS (thermospray): m/z [MNH₄ ⁺] 308.

Preparation 134-(3,5-Dichlorophenoxy)-5-ethyl-2-(2-hydroxyethyl)-2,4-dihydro-3H-pyrazol-3-one

A solution of 2-hydroxyethylhydrazine (4.30 g, 56.7 mmol) in glacialacetic acid (2.0 ml) was added to a stirred solution of the ketoester ofPreparation 12 (15.0 g, 51.5 mol) in glacial acetic acid (100 ml) andthe resulting solution was stirred at room temperature for 48 hours. Themixture was concentrated under reduced pressure and the crude productwas purified by flash column chromatography on silica gel eluting withdichloromethane:methanol (95:5, by volume) to provide the title compound(10.1 g) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.02 (t, 3H), 2.29 (m, 2H), 3.63 (m, 2H),3.80 (m, 2H), 6.92 (s, 2H), 7.21 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 317.

Microanalysis: Found: C, 48.86; H, 4.44; N, 9.01. C₁₃H₁₄N₂O₃Cl₂ requiresC, 49.23; H, 4.45; N, 8.83%.

Preparation 142-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-(3,5-dichlorophenoxy)-5-ethyl-2,4-dihydro-3H-pyrazol-3-one

tert-Butyldimethylsilyl chloride (8.14 g, 54.0 mmol) was added in oneportion to a stirred solution of the pyrazole of Preparation 13 (14.3 g,45.0 mmol) and imidazole (3.98 g, 58.5 mmol) in N,N-dimethylformamide(90 ml) and the resulting solution was stirred at room temperature for48 hours. The mixture was partitioned between ethyl acetate (100 ml) andwater (300 ml). The organic layer was separated, dried over magnesiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography on silica geleluting with dichloromethane:methanol (95:5, by volume) to provide thetitle compound (9.56 g) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=0.15 (s, 6H), 0.94 (s, 9H), 1.16 (t, 3H),2.45 (m, 2H), 3.94 (m, 4H), 6.85 (s, 2H), 6.97 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 431.

Microanalysis: Found: C, 52.87; H, 6.52; N, 6.46. C₁₉H₂₈N₂O₃Cl₂Sirequires C, 52.90; H, 6.54; N, 6.49%.

Preparation 151-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-5-yltrifluoromethanesulfonate

Phenyltriflamide (3.70 g, 10.5 mmol) was added in one portion to astirred solution of the pyrazole of Preparation 14 (4.10 g, 9.50 mmol)and triethylamine (1.60 ml, 11.4 mmol) in dichloromethane (20 ml) atroom temperature under nitrogen. The reaction was stirred for 2 hoursand then poured onto water (50 ml). The organic layer was separated,dried over magnesium sulphate, filtered and concentrated under reducedpressure. The crude product was purified by flash column chromatographyon silica gel eluting with dichloromethane to provide the title compound(5.10 g) as a purple oil.

¹H-NMR (300 MHz, CDCl₃): δ=0.01 (s, 6H), 0.86 (s, 9H), 1.17 (t, 3H),2.45 (q, 2H), 4.01 (m, 2H), 4.14 (m, 2H), 6.84 (s, 2H), 7.08 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 563.

Preparation 16 3-(1-Acetyl-2-oxopropoxy)-5-chlorobenzonitrile

A mixture of 3-chloro-2,4-pentanedione (6.73 g, 50.0 mmol), the phenolof Preparation 36 (7.67 g, 50.0 mmol), cesium carbonate (18.0 g, 55.4mmol) and acetone (40 ml) was heated under reflux for 2 hours. Thereaction was cooled to room temperature, N,N-dimethylformamide (6 ml)and acetone (30 ml) were added and the reaction was heated at 70° C. fora further 12 hours. After cooling, the solid was removed by filtrationand dissolved in 1M aqueous hydrochloric acid (150 ml). The resultingsolution was extracted with dichloromethane (3×100 ml) and the combinedorganic phases were washed with brine (30 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure to providethe title compound (5.50 g) as a brown solid, m.p. 105-108° C.

¹H-NMR (300 MHz, CDCl₃): δ=2.04 (s, 6H), 7.13 (s, 1H), 7.19 (s, 1H),7.35 (s, 1H), 14.40 (s, 1H).

Preparation 173-[(1-Acetyl-3,5-dimethyl-1H-pyrazol-4-yl)oxy]-5-chlorobenzonitrile

Sodium hydride (60% dispersion in oil, 840 mg, 21.0 mmol) was added to astirred solution of acetyl chloride (1.50 ml, 21.0 mmol) and thepyrazole of Example 76 (4.80 g, 19.4 mmol) in N,N-dimethylformamide (20ml) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 15minutes and then quenched by the addition of water (200 ml). Thereaction mixture was extracted with ethyl acetate (3×120 ml). Thecombined organic phases were washed with water (50 ml) and brine (50ml), dried over magnesium sulphate, filtered and concentrated underreduced pressure to leave a yellow solid. The crude product was purifiedby flash column chromatography on silica gel eluting withdichloromethane to provide the title compound (5.00 g) as a white solid,m.p.<60° C.

¹H-NMR (400 MHz, CDCl₃): δ=2.06 (s, 3H), 2.38 (s, 3H), 2.65 (s, 3H),6.99 (m, 1H), 7.08 (m, 1H), 7.29 (m, 1H).

LRMS (thermospray): m/z [MH⁺] 290.

Preparation 183-{[1-Acetyl-3-(bromomethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-5-chlorobenzonitrile

N-Bromosuccinimide (4.60 g, 25.6 mmol) was added to a stirred solutionof the pyrazole of Preparation 17 (5.00 g, 17.3 mmol) in1,1,1-trichloroethane (70 ml) and azobisisobutyronitrile (20 mg) at roomtemperature under nitrogen. The reaction was heated at 80° C. for 3hours and then cooled to room temperature. A second portion ofN-bromosuccinimide (2.00 g, 11.2 mmol) was added and the reactionmixture was heated at 80° C. for a further 4 hours. The reaction wascooled to room temperature and concentrated under reduced pressure andthe resulting yellow oil was purified by flash column chromatography onsilica gel eluting with pentane:dichloromethane (25:75, by volume) toprovide the title compound (2.30 g) as a white solid, m.p. 122-123° C.

¹H-NMR (300 MHz, CDCl₃): δ=2.10 (s, 3H), 2.74 (s, 3H), 4.73 (s, 2H),7.12 (s, 1H), 7.22 (s, 1H), 7.39 (s, 1H).

Preparation 19 3-Chloro-5,5-dimethyl-2,4-hexanedione

Chlorotrimethylsilane (26.8 ml, 0.21 mol) was added dropwise to astirred pale yellow solution of tetrabutylammonium bromide (1.139, 3.50mmol) in dry acetonitrile (100 ml) at room temperature under nitrogen.The resulting solution was cooled in ice and5,5-dimethylhexane-2,4-dione (10.0 g, 70.4 mmol) and then drydimethylsulphoxide (14.7 ml, 0.21 mol) were added dropwise over 5minutes producing a yellow solution which was allowed to warm slowly toroom temperature with stirring over 3 hours. The mixture was dilutedwith water (1000 ml) and stirred for 10 min and then extracted withether (1×500 ml, 2×250 ml). The combined ether layers were dried overmagnesium sulphate, filtered and concentrated under reduced pressure toleave a yellow oil. The crude product was purified by distillation underreduced pressure to provide the title compound (10.0 g) as a pale yellowoil, b.p. 220-225° C./60 mmHg.

¹H-NMR (400 MHz, CDCl₃): δ=1.25 (s, 9H), 2.39 (s, 3H), 5.10 (s, 1H).

LRMS (thermospray): m/z [MNH₄ ⁺] 194.

Preparation 20 4-[(Methylamino)methyl]benzonitrile

4-Cyanobenzaldehyde (12.0 g, 92.0 mmol), methylamine (69 ml of a 2.0Msolution in tetrahydrofuran, 137 mmol) and magnesium sulphate (45 g)were stirred in dichloromethane (300 ml) at room temperature for 5 days.The mixture was filtered and the filtrate was concentrated under reducedpressure to leave a yellow oil. The oil was dissolved in methanol (200ml) and sodium borohydride (4.10 g, 109 mmol) was added cautiously withvigorous stirring. Once the addition was complete the reaction wasstirred for 1 hour and the mixture was concentrated under reducedpressure. The residue was dissolved in 1M aqueous sodium hydroxidesolution (200 ml) and the mixture was stirred at room temperature for 1hour. The resulting solution was extracted with dichloromethane (2×200ml) and the combined organic phases were dried over magnesium sulphate,filtered and concentrated under reduced pressure to provide the titlecompound (13.4 g) as a pale yellow oil.

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (s, 1H), 2.46 (s, 3H), 3.82 (s, 2H),7.47 (d, 2H), 7.64 (d, 2H).

LRMS (electrospray): m/z [MH⁺] 147.

Preparation 21 4-{[(2-Hydroxyethyl)amino]methyl}benzonitrile

A mixture of 4-Cyanobenzaldehyde (14.1 g, 107 mmol), ethanolamine (6.56g, 107 mmol) and toluene (100 ml) was heated under reflux for 14 hoursusing a Dean-Stark apparatus to remove water. The reaction was cooled toroom temperature and concentrated under reduced pressure to leave ayellow oil. The oil was dissolved in dichloromethane (200 ml), cooled to0° C. and triethylamine (16.3 ml, 117 mmol) and chlorotrimethylsilane(14.9 ml, 117 mmol) were added dropwise. A white precipitate formed andafter stirring for 1 hour the mixture was filtered. The filtrate wasconcentrated under reduced pressure to leave an orange solid (25.0 g).The orange solid was dissolved in methanol (200 ml) and sodiumborohydride (4.50 g, 122 mmol) was added cautiously with vigorousstirring. Once the addition was complete the reaction was stirred for 1hour and the mixture was then concentrated under reduced pressure. Theresidue was dissolved in 1M aqueous sodium hydroxide solution (200 ml)and the mixture was stirred at room temperature for 1 hour. Theresulting solution was extracted with dichloromethane (3×200 ml) and thecombined organic phases were dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified byflash column chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (12.0 g) as a pale yellow oil which solidified onstanding to leave a yellow solid, m.p.<60° C.

¹H-NMR (300 MHz, CDCl₃): δ=1.84 (s, 2H), 2.84 (t, 2H), 3.68 (t, 2H),3.89 (s, 2H), 7.45 (d, 2H), 7.65 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 177.

Preparation 22N-{[1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]methyl}-N-(3-pyridinylmethyl)amine

3-(Methylamino)pyridine (327 mg, 3.04 mmol) was added in one portion toa stirred solution of the bromide of Preparation 28 (300 mg, 0.610 mmol)in isopropanol (5 ml) at room temperature. The mixture was heated at 50°C. for 1 hour, cooled to room temperature and concentrated under reducedpressure to leave an orange oil. The crude product was purified by flashcolumn chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:4:1, by volume) to provide thetitle compound (50 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=0.15 (s, 6H), 0.77 (s, 9H), 2.02 (s, 3H),3.64 (s, 2H), 3.70 (s, 2H), 3.95 (t, 2H), 4.17 (t, 2H), 6.75 (s, 2H),6.97 (s, 1H), 7.15 (dd, 1H), 7.53 (d, 1H), 8.47 (m, 2H).

LRMS (thermospray): m/z [MH⁺] 521.

Preparation 23 3-Chloro-5-methyl-2,4-hexanedione

Chlorotrimethylsilane (13.4 ml, 105 mmol) was added dropwise to astirred pale yellow solution of tetrabutylammonium iodide (566 mg, 1.53mmol) in dry acetonitrile (100 ml) at room temperature under nitrogen.The resulting solution was cooled in ice and 5-methylhexane-2,4-dione(4.50 g, 35.1 mmol) and then dry dimethylsulphoxide (7.47 ml, 105 mmol)were added dropwise over 5 minutes producing a yellow solution which wasallowed to warm slowly to room temperature with stirring over 1 hour.Tetrabutylammonium bromide (566 mg, 1.75 mmol) was then added in oneportion and the reaction was stirred at room temperature for 2 hours.The mixture was diluted with water (200 ml), stirred for 10 min and thenextracted with ether (3×100 ml). The combined ether layers were driedover magnesium sulphate, filtered and concentrated under reducedpressure to leave a yellow oil. The crude product was purified by flashcolumn chromatography on silica gel eluting with pentane:ethyl acetate(98:2, by volume) to provide the title compound (2.00 g) as a colourlessoil.

¹H-NMR (400 MHz, CDCl₃): δ=1.15 (d, 6H), 2.29 (s, 3H), 3.25 (sept, 1H),15.60 (s, 1H).

LRMS (thermospray): m/z [MNH₄ ⁺] 180.

Preparation 24 5-(1-Acetyl-3-methyl-2-oxobutoxy)isophthalonitrile

A mixture of the dione of Preparation 23 (1.12 g, 6.94 mmol), the phenolof Preparation 39 (1.00 g, 6.94 mmol), cesium carbonate (2.25 g, 6.94mmol) and acetone (30 ml) was heated under reflux for 4 hours. Thereaction was cooled to room temperature and concentrated under reducedpressure to leave a brown solid. The solid was dissolved in 1M aqueoushydrochloric acid (50 ml) and the solution was extracted withdichloromethane (3×30 ml). The combined organic phases were washed withbrine (30 ml), dried over magnesium sulphate, filtered and concentratedunder reduced pressure. The crude product was purified by flash columnchromatography on silica gel eluting with pentane:ethyl acetate (90:10,by volume) to provide the title compound (580 mg) as a yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ=1.08 (d, 6H), 2.02 (s, 3H), 2.24 (sept, 1H),7.47 (s, 2H), 7.63 (s, 1H), 14.71 (s, 1H).

LRMS (electrospray): m/z [M-H⁺] 269.

Preparation 255-{[1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]oxy}isophthalonitrile

Sodium hydride (60% dispersion in oil, 45 mg, 1.12 mmol) was added to astirred solution of 2-bromoethoxy-t-butyldimethylsilane (270 mg, 1.12mmol) and the pyrazole of Example 95 (250 mg, 0.930 mmol) inN,N-dimethylformamide (5 ml) at 0° C. under nitrogen. The reaction waswarmed to room temperature and stirred for 12 hours. The reactionmixture was quenched by the addition of water (50 ml) and the aqueousphase was extracted with ethyl acetate (3×30 ml). The combined organicphases were dried over magnesium sulphate, filtered and concentratedunder reduced pressure to leave a brown oil. The crude product waspurified by flash column chromatography on silica gel elutingpentane:ethyl acetate (80:20, by volume) to provide the title compound(60 mg) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=0.02 (s, 6H), 0.85 (s, 9H), 1.19 (d, 6H),2.09 (s, 3H), 2.79 (sept, 1H), 3.99 (m, 2H), 4.10 (m, 2H), 7.39 (s, 2H),7.57 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 425.

Preparation 26 di(tert-Butyl)2-[4-(3,5-dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yl]ethylimidodicarbonateanddi(tert-butyl)-2-[4-(3,5-dichlorophenoxy)-5-ethyl-1H-pyrazol-1-yl]ethylimidodicarbonate

Di-t-butyldicarbonate (14.0 g, 64.2 mmol) and 4,4-dimethylaminopyridine(630 mg, 5.14 mmol) were added portionwise to a stirred solution of theamines of Example 283 (7.72 g, 25.7 mmol) in acetonitrile (128 ml) atroom temperature under nitrogen. The reaction was stirred for 14 hoursand concentrated under reduced pressure. A solution of the residue indichloromethane (300 ml) was washed with water (100 ml), dried overmagnesium sulphate, filtered and concentrated under reduced pressure.The crude product was purified by flash chromatography on silica geleluting with dichloromethane:methanol (99:1, by volume) to afford thetitle compounds (12.3 g) in a 85:15 ratio of regioisomers as acolourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=1.15 (major, t, 3H), 1.15 (minor, t, 3H),1.52 (major, s, 18H), 1.52 (minor, s, 18H), 2.47 (major, q, 2H), 2.56(minor, q, 2H), 4.00 (major, t, 2H), 4.00 (minor, t, 2H), 4.24 (major,t, 2H), 4.24 (minor, t, 2H), 6.85 (major, s, 2H), 6.85 (minor, s, 2H),7.00 (major, s, 1H), 7.00 (minor, s, 1H), 7.21 (major, s, 1H), 7.25(minor, s, 1H).

LRMS (thermospray): m/z [MH⁺] 500.

Microanalysis: Found: C, 54.94; H, 6.26; N, 8.27. C₂₃H₃₁Cl₂N₃O₅ requiresC, 55.20; H, 6.24; N, 8.40%.

Preparation 271-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-(3,5-dichlorophenoxy)-3,5-dimethyl-1H-pyrazole

Chloro-t-butyldimethylsilane (1.93 g, 12.8 mmol) was added in oneportion to a stirred solution of the pyrazole of Example 1 (3.50 g, 11.6mmol) and imidazole (1.03 g, 15.1 mmol) in N,N-dimethylformamide (23 ml)at room temperature under nitrogen. The reaction was stirred for 2 daysand water (200 ml) was added. The aqueous phase was extracted withdiethyl ether (3×200 ml) and the combined organic phases were washedwith water (2×50 ml) and brine (2×50 ml), dried over magnesium sulphate,filtered and concentrated under reduced pressure. The crude product waspurified by flash chromatography on silica gel eluting withpentane:ethyl acetate (80:20, by volume) to provide the title compound(4.82 g) as a colourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=0.09 (s, 6H), 0.78 (s, 9H), 2.01 (s, 3H),2.05 (s, 3H), 3.88 (q, 2H), 4.02 (q, 2H), 6.76 (s, 2H), 6.88 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 415.

Preparation 285-(Bromomethyl)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazole

N-Bromosuccinimide (640 mg, 3.60 mmol) was added to a stirred solutionof the pyrazole of Preparation 27 (1.00 g, 2.40 mmol) in carbontetrachloride (15 ml) and azobisisobutyronitrile (20 mg) at roomtemperature under nitrogen. The reaction was heated under reflux for 5hours then cooled to room temperature and filtered. The filtrate wasconcentrated under reduced pressure and the crude product was purifiedby flash column chromatography on silica gel eluting withdichloromethane:methanol:ammonia (97:2.5:0.5, by volume) to provide thetitle compound (300 mg) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=0.04 (s, 6H), 0.82 (s, 9H), 2.02 (s, 3H),3.96 (m, 2H), 4.22 (m, 2H), 4.41 (s, 2H), 6.81 (s, 2H), 7.01 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 495.

Preparation 293-{[1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,5-dimethyl-1H-pyrazol-4-yl]oxy}-5-chlorobenzonitrile

Chloro-t-butyldimethylsilane (2.78 g, 18.5 mmol) was added in oneportion to a stirred solution of the pyrazole of Example 114 (4.89 g,16.8 mmol) and imidazole (1.48 g, 21.8 mmol) in N,N-dimethylformamide(30 ml) at room temperature under nitrogen. The reaction was stirred for3 days and water (200 ml) was added. The aqueous phase was extractedwith diethyl ether (3×200 ml) and the combined organic phases werewashed with water (2×50 ml) and brine (2×50 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography on silica gel eluting withdichloromethane to provide the title compound (5.60 g) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ=−0.02 (s, 6H), 0.82 (s, 9H), 2.02 (s, 3H),2.12 (s, 3H), 3.97 (q, 2H), 4.06 (m, 2H), 7.02 (s, 1H), 7.11 (s, 1H),7.24 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 408.

Microanalysis: Found: C, 58.95; H, 6.96; N, 10.22. C₂₀H₂₈N₃O₂ClSirequires C, 59.13; H, 6.95; N, 10.35%.

Preparation 303-{[5-(Bromomethyl)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-methyl-1H-pyrazol-4-yl]oxy}-5-chlorobenzonitrile

N-Bromosuccinimide (2.44 g, 13.7 mmol) was added to a stirred solutionof the pyrazole of Preparation 29 (5.56 g, 13.7 mmol) in carbontetrachloride (50 ml) and azobisisobutyronitrile (20 mg) at roomtemperature under nitrogen. The reaction was heated under reflux for 1hour, cooled to room temperature and concentrated under reducedpressure. The crude product was purified by flash column chromatographyon silica gel eluting with pentane:dichloromethane acetate (75:25, byvolume) to provide the title compound (3.00 g) as a colourless oil.

¹H-NMR (300 MHz, CDCl₃): δ=−0.02 (s, 6H), 0.83 (s, 9H), 2.04 (s, 3H),3.97 (q, 2H), 4.25 (m, 2H), 4.43 (s, 2H), 7.09 (s, 1H), 7.18 (s, 1H),7.33 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 486.

Preparation 313-{[5-(Aminomethyl)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-methyl-1H-pyrazol-4-yl]oxy}-5-chlorobenzonitrile

The bromide of Preparation 30 (1.58 g, 3.26 mmol) was added to asaturated solution of ammonia in isopropanol (50 ml) at 0° C. Thereaction was stirred for 6 hours and allowed to slowly warm to roomtemperature. The mixture was concentrated under reduced pressure and theresulting yellow oil was dissolved in dichloromethane (50 ml). Thesolution was washed with 1M aqueous sodium carbonate solution (2×20 ml)and brine (20 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure to provide the title compound (1.00g) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃): δ=−0.23 (s, 6H), 0.62 (s, 9H), 1.22 (s, 2H),1.82 (s, 3H), 2.56 (s, 2H), 3.78 (m, 2H), 4.02 (m, 2H), 6.85 (s, 1H),6.96 (s, 1H), 7.06 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 421.

Preparation 32 1-Bromo-3-chloro-5-methoxybenzene

Sodium methoxide (2.20 ml of a 4.5M solution in methanol, 10.0 mmol) wasadded dropwise to a stirred solution of 1-fluoro-3-chloro-5-bromobenzene(1.00 g, 4.77 mmol) in methanol (28 ml) at room temperature undernitrogen. The reaction was heated under reflux for 3 days and cooled toroom temperature. The mixture was concentrated under reduced pressureand the resulting yellow oil was dissolved in dichloromethane (30 ml).The resulting solution was washed with water (2×20 ml) dried overmagnesium sulphate, filtered and concentrated under reduced pressure.The crude product was purified by flash column chromatography on silicagel eluting with cyclohexane to provide the title compound (302 mg) as acolourless oil.

¹H-NMR (400 MHz, CDCl₃): δ=3.77 (s, 3H), 6.82 (s, 1H), 6.94 (s, 1H),7.09 (s, 1H).

Microanalysis: Found: C, 37.94; H, 2.75. C₇H₆BrClO requires C, 37.96; H,2.73%.

Preparation 33 3-Fluoro-5-methoxybenzonitrile

Sodium methoxide (1.50 ml of a 4.5M solution in methanol, 7.10 mmol) wasadded dropwise to a stirred solution of 3,5-difluorobenzonitrile (1.00g, 7.10 mmol) in N,N-dimethylformamide (36 ml) at 0° C. under nitrogen.The reaction was allowed to warm to room temperature and stirred for 14hours. The reaction was diluted with ether (40 ml), washed with water(3×100 ml) and brine (100 ml), dried over magnesium sulphate, filteredand concentrated under reduced pressure. The crude product was purifiedby flash chromatography on silica gel eluting with cyclohexane:ethylacetate (95:5, by volume) to provide the title compound (418 mg) as ayellow oil.

¹H-NMR (400 MHz, CDCl₃): δ=3.84 (s, 3H), 6.82 (dd, 1H), 6.95 (dd, 1H),6.96 (s, 1H).

LRMS (thermospray): m/z [MNH₄ ⁺] 169.

Microanalysis: Found: C, 63.46; H, 3.95; N, 9.14. C₈H₆NOF requires C,63.58; H, 4.00; N, 9.27%.

Preparation 34 3-Fluoro-5-hydroxybenzonitrile

Boron trichloride (1.65 ml of a 1.0M solution in dichloromethane, 1.65mmol) was added dropwise to a stirred solution of the nitrile ofPreparation 33 (100 mg, 0.660 mmol) and tetrabutylammonium iodide (268mg, 0.728 mmol) in dichloromethane (3 ml) at −78° C. The reaction wasallowed to warm 0° C., stirred for 2 hours and then allowed to warm toroom temperature and stirred for 14 hours. The reaction was cooled to 0°C., cautiously quenched with ice and then concentrated under reducedpressure. The residue was dissolved in ether (40 ml) and the resultingsolution was washed with water (3×40 ml) and brine (40 ml), dried overmagnesium sulphate, filtered and concentrated under reduced pressure.The crude product was purified by flash chromatography on silica geleluting with cyclohexane:ethyl acetate (90:10, by volume) to provide thetitle compound (50 mg) as a white solid, m.p. 138-139° C.

¹H-NMR (300 MHz, CDCl₃): δ=5.81 (s, 1H), 6.80 (dd, 1H), 6.94 (dd, 1H),6.95 (s, 1H).

Microanalysis: Found: C, 60.99; H, 3.01; N, 10.16. C₇H₄NOF requires C,61.32; H, 2.94; N, 10.22%.

Preparation 35 3-Chloro-5-methoxybenzonitrile

Palladiumtetrakis(triphenylphosphine) (174 mg, 0.150 mmol) was added inone portion to a stirred solution of the bromide of Preparation 32 (500mg, 2.26 mmol) and zinc cyanide (146 mg, 1.24 mmol) inN,N-dimethylformamide (3 ml) at room temperature under nitrogen. Thereaction was heated at 100° C. for 14 hours and cooled to roomtemperature. The mixture was concentrated under reduced pressure and thecrude product was purified by flash chromatography on silica gel elutingwith cyclohexane:ethyl acetate (95:5, by volume) to provide the titlecompound (380 mg) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃): δ=3.82 (3H, s), 7.04 (s, 1H), 7.12 (s, 1H),7.23 (s, 1H).

Microanalysis: Found: C, 57.50; H, 3.63; N, 8.16. C₈H₆NOCl requires C,57.33; H, 3.61; N, 8.36%.

Preparation 36 3-Chloro-5-hydroxybenzonitrile

Boron trichloride (26.0 ml of a 1.0M solution in dichloromethane, 26.0mmol) was added dropwise to a stirred solution of the nitrile ofPreparation 35 (1.80 g, 10.0 mmol) and tetrabutylammonium iodide (4.36g, 11.0 mmol) in dichloromethane (50 ml) at −78° C. The reaction wasallowed to warm to room temperature and stirred for 14 hours. Thereaction was cooled to 0° C., cautiously quenched with ice and dilutedwith dichloromethane (100 ml). The organic phase was washed with water(3×40 ml) and brine (40 ml), dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel eluting with cyclohexane:ethylacetate (80:20, by volume) to provide the title compound (900 mg) as awhite solid.

¹H-NMR (400 MHz, d₆DMSO): δ=7.12 (m, 2H), 7.38 (s, 1H), 10.65 (s, 1H).

Microanalysis: Found: C, 54.76; H, 2.81; N, 8.94. C₇H₄NOCl requires C,54.75; H, 2.63; N, 9.12%.

Preparation 37 1,3-Dibromo-5-methoxybenzene

Sodium methoxide (8.80 ml of a 4.5M solution in methanol, 41.0 mmol) wasadded dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00g, 19.0 mmol) in N,N-dimethylformamide (95 ml) at 0° C. under nitrogen.The reaction was allowed to warm to room temperature, stirred for 1 hourand then concentrated under reduced pressure. The residue was dissolvedin ether and the resulting solution was washed with water (3×300 ml) andbrine (300 ml), dried over magnesium sulphate, filtered and concentratedunder reduced pressure to provide the title compound (5.13 g) as a whitesolid.

¹H-NMR (300 MHz, CDCl₃): δ=3.79 (s, 3H), 7.00 (s, 2H), 7.26 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 266.

Microanalysis: Found: C, 31.56; H, 2.29. C₇H₆OBr₂ requires C, 31.62; H,2.27%.

Preparation 38 3,5-Dicyanomethoxybenzene

Tris(dibenzylideneacetone)dipalladium (6.53 g, 7.15 mmol) was added inone portion to a stirred solution of the bromide of Preparation 37 (38.0g, 143 mmol) and zinc cyanide (20.0 g, 172 mmol) inN,N-dimethylformamide (300 ml) at room temperature under nitrogen. Thereaction was heated at 100° C. for 14 hours and cooled to roomtemperature. Water (1500 ml) was added and the mixture was extractedwith ethyl acetate (3×500 ml). The combined organics were filtered andthe filtrate was washed with water (500 ml), dried over magnesiumsulphate, filtered and concentrated under reduced pressure. Theresulting solid was triturated with toluene (1000 ml) to provide thetitle compound (18.0 g) as a tan solid.

¹H-NMR (300 MHz, CDCl₃): δ=3.83 (3H, s), 7.31 (2H, s), 7.48 (1H, s).

Preparation 39 3,5-Dicyanohydroxybenzene

The nitrile of Preparation 38 (9.60 g, 60.7 mmol) was added portionwiseto a stirred suspension of aluminium trichloride (32.4 g, 243 mmol) indichloromethane (250 ml) at 0° C. under nitrogen. The suspension washeated to 45° C. and stirred for 6 days. The reaction was cooled to roomtemperature and cautiously poured onto ice (450 ml). Concentratedhydrochloric acid (450 ml) was added dropwise and the resultingsuspension was stirred for 10 minutes at room temperature. The resultingsolid was collected by filtration, washed with water and dried overphosphorus pentoxide to provide the title compound (7.83 g) as a tansolid containing approximately 11% starting material by ¹H-NMR andmicroanalysis.

¹H-NMR (400 MHz, CDCl₃): δ=7.36 (m, 2H), 7.56 (m, 1H).

Preparation 40 3-Methoxy-5-methylphenyl trifluoromethanesulfonate

Trifluoromethanesulphonic anhydride (2.02 ml, 12.0 mmol) was addeddropwise to a stirred solution of 3-methoxy-5-methylphenol (1.50 g, 10.9mmol) in pyridine (20 ml) at −20° C. under nitrogen. The reaction waswarmed to 0° C., stirred for 90 minutes and re-cooled to −20° C. Moretrifluoromethanesulphonic anhydride (1.01 ml, 6.00 mmol) was addeddropwise. The reaction was allowed to warm to room

temperature, stirred for 14 hours and cautiously poured into water (100ml). The aqueous phase was extracted with ether (150 ml) and the organicphases were washed with water (3×75 ml), 0.2M hydrochloric acid (3×75ml), 1.0M aqueous sodium carbonate solution (2×75 ml), water (75 ml) andbrine (75 ml), dried over magnesium sulphate, filtered and concentratedunder reduced pressure to provide the title compound (2.86 g) as a palebrown oil.

¹H-NMR (400 MHz, CDCl₃): δ=2.35 (s, 3H), 3.80 (s, 3H), 6.60 (s, 1H),6.68 (s, 1H), 6.73 (s, 1H).

Preparation 41 3-Methoxy-5-methylbenzonitrile

The triflate of Preparation 40 (1.94 g, 7.10 mmol),dibromobis(triphenylphosphine)nickel (369 mg, 0.490 mmol),1,1′-bis(diphenylphosphino)ferrocene (331 mg, 0.590 mmol) and potassiumcyanide (1.38 g, 21.3 mmol) were added consecutively to a stirredsuspension of Rieke® zinc (supplied by the Aldrich chemical company as asuspension; 5 g Zinc in 100 ml tetrahydrofuran) (74 mg, 1.14 mmol) inacetonitrile (4 ml) at room temperature. The reaction was heated to 75°C. for 8 hours and then cooled to room temperature. The mixture waspartitioned between ether (200 ml) and water (150 ml) and the organicphase was separated, washed with water (2×100 ml) and brine (75 ml),dried over magnesium sulphate, filtered and concentrated under reducedpressure to give a pale brown oil. The crude product was purified byflash chromatography on silica gel eluting with pentane:ethyl acetate(85:15, by volume) to provide the title compound (815 mg) as a whitesolid.

¹H-NMR (400 MHz, CDCl₃): δ=2.34 (s, 3H), 3.80 (s, 3H), 6.93 (s, 1H),6.94 (s, 1H), 7.04 (s, 1H).

Preparation 42 3-Hydroxy-5-methylbenzonitrile

Boron trichloride (17.6 ml of a 1.0M solution in dichloromethane, 17.6mmol) was added dropwise to a stirred solution of the nitrile ofPreparation 41 (866 mg, 5.88 mmol) and tetrabutylammonium iodide (2.61g, 7.05 mmol) in dichloromethane (50 ml) at −78° C. The reaction wasallowed to warm to room temperature and stirred for 20 minutes. Thereaction was cooled to 0° C., cautiously quenched with ice and dilutedwith dichloromethane (100 ml). The organic phase was separated, driedover magnesium sulphate, filtered and concentrated under reducedpressure. The crude product was purified by flash chromatography onsilica gel eluting with pentane:ethyl acetate (50:50, by volume) toprovide the title compound (677 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ=2.32 (s, 3H), 5.05 (s, 1H), 6.88 (s, 1H),6.90 (s, 1H), 7.04 (s, 1H).

Preparations 43 to 46

The compounds of the following tabulated Preparations of the generalformula:

were prepared by a similar method to that of Preparation 9 using theappropriate phenol starting material and the chloride of Preparation 2.

Preparation No. (Phenol No.) R LRMS Analytical Data 43 F m/z [MNH₄ ⁺]281. ¹H-NMR (300 MHz, CDCl₃): δ = 1.05 (t, 6H), 2.27 (q, 4H), 6.89 (m,1H), (Phenol (thermospray) 7.03 (s, 1H), 7.04 (m, 1H). Preparation 34)44 Me m/z [M − H⁺] 258. ¹H-NMR (400 MHz, CDCl₃): δ = 1.09 (t, 6H), 2.32(q, 4H), 2.37 (s, 3H), (Phenol (electrospray) 6.96 (s, 1H), 6.97 (s,1H), 7.15 (s, 1H), 14.50 (s, 1H). Preparation 42) 45 CN m/z [M − H⁺]269. ¹H-NMR (300 MHz, CDCl₃): δ = 1.09 (m, 6H), 2.30 (m, 4H), 7.42 (s,(Phenol (electrospray) 2H), 7.61 (s, 1H), 14.56 (s, 1H). Preparation 39)46 Cl m/z [MH⁺] 280. ¹H-NMR (400 MHz, CDCl₃): δ = 1.08 (m, 6H), 2.31 (q,4H), 7.12 (s, (Phenol (thermospray) 1H), 7.19 (s, 1H), 7.31 (s, 1H).Preparation 36)

Preparation 47 1-Cyclopropyl-1,3-pentanedione

A stirred suspension of magnesium turnings (1.83 g, 75.0 mmol) inmethanol (85 ml) was heated under reflux for 90 minutes. The suspensionwas cooled to room temperature and a solution of 3-ketopentanoic acid(17.4 g, 150.0 mmol) in methanol (15 ml) was added. The white suspensiondissolved to give a pale yellow solution. The reaction was stirred atroom temperature for 1 hour and then concentrated under reduced pressureto give a pale yellow solid which was dissolved in N,N-dimethylformamide(50 ml). In a separate flask carbonyldiimidazole (13.4 g, 83.0 mmol) wasadded portionwise to a stirred solution of cyclopropanecarboxylic acid(6.46 g, 75.0 mmol) in N,N-dimethylformamide (150 ml) at roomtemperature under nitrogen. The reaction was stirred for 90 minutes andthen the magnesium salt previously prepared was added dropwise. Thereaction was stirred for 3 days and then poured into 1.0M hydrochloricacid (150 ml). The aqueous phase was extracted with ether (3×200 ml) andthe combined organic phases were dried over magnesium sulphate, filteredand concentrated under reduced pressure. The crude product was purifiedby flash chromatography on silica gel eluting with pentane:ethyl acetate(90:10, by volume) to provide the title compound (9.33 g) as a yellowoil.

¹H-NMR (400 MHz, CDCl₃): keto and enol forms present with enol as majorcomponent; enol signals δ=1.00 (m, 7H), 1.60 (m, 1H), 2.25 (m, 2H), 5.59(s, 1H), 15.62 (s, 1H); keto signals δ=1.00 (m, 7H), 2.01 (m, 1H), 2.52(m, 2H), 3.68 (s, 2H).

LRMS (electrospray): m/z [M-H⁺] 139.

Microanalysis: Found: C, 68.35; H, 8.72. C₈H₁₂O₂ requires C, 68.55; H,8.63%.

Preparation 48

The compound of the following tabulated Preparation of the generalformula:

was prepared by a similar method to that of Preparation 47 using theappropriate ketoacid and carboxylic acid starting materials.

Preparation No. R R′ LRMS Analytical Data 48 iPr Et m/z [M − H⁺] 141.¹H-NMR (400 MHz, CDCl₃): keto and enol forms present with enol(electrospray) major δ = 1.12 (m, 18H, keto and enol), 2.32 (m, 4H, ketoand enol), 2.49 (m, 2H, keto and enol), 3.61 (s, 2H, keto), 5.49 (s, 1H,enol), 15.52 (s, 1H, enol). Microanalysis: Found: C, 67.22; H, 9.95.C₈H₁₄O₂ requires C, 67.57; H, 9.92%.

Preparations 49 to 51

The compounds of the following tabulated Preparations of the generalformula:

were prepared by a similar method to that of Preparation 2 using theappropriate diketone starting material.

Preparation No. (Diketone No.) R R′ LRMS Analytical Data 49 cycloPr Etm/z [M − H⁺] 173. ¹H-NMR (400 MHz, CDCl₃): 1.10 (m, 7H), 2.41 (m, 1H),2.61 (m, 2H), (Preparation 47) (electrospray) 15.90 (s, 1H). 50 Me Etm/z [MNH₄ ⁺] 166. ¹H-NMR (300 MHz, CDCl₃): 1.19 (m, 3H), 2.27 (s, 3H),2.67 (q, 2H), (Commercially (thermospray) 15.40 (s, 1H). availablediketone used) 51 iPr Et m/z [M − H⁺] 175. ¹H-NMR (400 MHz, CDCl₃): 1.18(m, 9H), 2.64 (q, 2H), 3.20 (m, 1H), (Preparation 48) (electrospray)15.80 (s, 1H).

Preparations 52 to 54

The compounds of the following tabulated Preparations of the generalformula:

were prepared by a similar method to that of Preparation 9 using theappropriate diketone starting material and the phenol of Preparation 39.

Preparation No. (Diketone No.) R R′ LRMS Analytical Data 52 cycloPr Etm/z [M − H⁺] 282. ¹H-NMR (400 MHz, CDCl₃): 0.93 (m, 2H), 1.12 (t, 3H),1.21 (m, 2H), (Preparation 49) (electrospray) 1.78 (m, 1H), 2.29 (q,2H), 7.49 (s, 2H), 7.61 (s, 1H), 14.87 (s, 1H). 53 tBu Me m/z [MNH₄ ⁺]301. ¹H-NMR (400 MHz, CDCl₃): 1.08 (s, 9H), 1.84 (s, 3H), 7.30 (s, 1H),(Preparation 19) (thermospray) 7.57 (s, 2H), 15.42 (s, 1H). 54 iPr Etm/z [M − H⁺] 283. ¹H-NMR (400 MHz, CDCl₃): 1.03 (m, 9H), 2.23 (q, 2H),2.58 (m, 1H), (Preparation 51) (electrospray) 7.41 (s, 2H), 7.59 (s,1H), 14.63 (s, 1H)

Preparation 55 4-(Aminomethyl)benzamide

Powdered potassium hydroxide (340 mg, 6 mmol) was added in one portionto a stirred solution of 4-(aminomethyl)benzonitrile (200 mg, 1.5 mmol)in 2-methyl-2-propanol (20 ml) at reflux under nitrogen. The reactionwas heated at reflux for 30 minutes and cooled to room temperature. Themixture was concentrated under reduced pressure and the crude productwas purified by flash chromatography on silica gel eluting withdichloromethane:methanol:ammonia (95:5:0.5, by volume) to provide thetitle compound (150 mg) as a white solid.

¹H-NMR (300 MHz, CD₃OD): δ=3.85 (s, 2H), 7.43 (d, 2H), 7.82 (d, 2H).

LRMS (thermospray): m/z [MH⁺] 151.

Preparation 56 3-Oxopentanoic acid

Sodium hydroxide (54 g, 1.35 mol) was added portionwise to a solution of3-oxo-pentanoic acid methyl ester (80 g, 0.62 mol) in tetrahydrofuran(300 ml) and water (300 ml) at 0° C. The reaction was allowed to warm toroom temperature and was stirred for 18 hours. The reaction mixture waswashed with diethylether (500 ml) and the aqueous phase was acidified topH1 at 0° C. with concentrated hydrochloric acid (140 ml). The aqueousphase was extracted with dichloromethane (2×300 ml) and the combinedorganic extracts dried over magnesium sulphate and concentrated underreduced pressure to provide the title compound (44 g) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ=1.12 (t, 3H), 2.59 (q, 2H), 3.49 (s, 2H).

Preparation 57 3-(Benzyloxy)propanoic acid

Sodium metal (249 mg, 10.8 mmol) was added to benzyl alcohol (30 g, 278mmol) at room temperature under nitrogen and the reaction was stirredfor 30 minutes. Methyl acrylate (25.9 ml, 259 mmol) was then addeddropwise and the reaction was stirred at room temperature for 18 h.After quenching with saturated aqueous ammonium chloride solution (200ml) the mixture was extracted with ethyl acetate (2×300 ml) and thecombined organic extracts were washed with brine (100 ml), dried overmagnesium sulphate and concentrated under reduced pressure. The residualoil was dissolved in ethanol (300 ml) and 1M aqueous sodium hydroxidesolution (300 ml) was added dropwise. After 3 hours the ethanol wasremoved under reduced pressure and the aqueous residue was washed withdichloromethane (200 ml). The aqueous phase was then acidified with 2Naqueous hydrochloric acid (150 ml), extracted with dichloromethane(2×250 ml) and the combined organic extracts were dried over magnesiumsulphate and concentrated under reduced pressure. The residual oil wasdissolved in 10% aqueous potassium carbonate solution (300 ml), washedwith diethylether (300 ml) and the aqueous phase was acidified to pH1using concentrated hydrochloric acid. The mixture was then extractedwith dichloromethane (2×300 ml) and the combined organic extracts weredried over magnesium sulphate and concentrated under reduced pressure toprovide the title compound (44.4 g) as a colourless oil.

¹H NMR (300 MHz, CDCl₃): δ=2.67 (t, 2H), 3.89 (t, 2H), 4.58 (s, 2H),7.18 (m, 5H).

Preparation 58 (4Z)-1-(Benzyloxy)-5-hydroxy-4-hepten-3-one

A suspension of magnesium turnings (1.74 g, 71.6 mmol) in methanol (85ml) was heated to reflux under nitrogen for 1.5 hours, cooled to roomtemperature and the β-keto acid from Preparation 56 (16.6 g, 143 mmol)was added. The reaction was stirred for 1.5 hours and the solvent wasremoved under reduced pressure to give the magnesium salt of the acid asa white solid. Meanwhile, the acid from Preparation 57 (12.9 g, 71.6mmol) was dissolved in dimethylformamide (150 ml) andcarbonyldiimidazole (12.8 g, 78.8 mmol) was added portionwise undernitrogen at room temperature. This was stirred for 1 hour and themagnesium salt from above was added as a solution in dimethylformamide(50 ml). Evolution of gas was noted, and the reaction was allowed tostir at room temperature for 18 hours. The mixture was concentratedunder reduced pressure and the residual orange oil was dissolved indichloromethane (300 ml), washed with 0.5M aqueous hydrochloric acid(250 ml) containing methanol (10 ml) and the aqueous phase was separatedand extracted with dichloromethane (2×300 ml). The combined organicextracts were washed with brine (300 ml) containing methanol (20 ml),dried over magnesium sulphate and concentrated under reduced pressure.The residual orange oil was purified by flash chromatography on silicagel eluting with cyclohexane:ethyl acetate (80:20, by volume) to providethe title compound (12.0 g) as an orange oil.

¹H NMR (400 MHz, CDCl₃): δ=1.17 (t, 3H), 2.33 (q, 2H), 2.58 (t, 2H),3.76 (t, 2H), 4.53 (s, 2H), 5.57 (s. 1H), 7.13 (m, 5H).

LRMS (electrospray): m/z [MNa⁺] 257.

Microanalysis: Found C, 71.77; H, 7.74. Cl₁₄H₁₈O₃ requires C, 71.76: H,7.69%.

Preparation 59 (4E)-1-(Benzyloxy)-4-chloro-5-hydroxy-4-hepten-3-one

Trimethylsilyl chloride (10 ml, 51.3 mmol) was added to a solution ofthe enol from Preparation 58 (4.0 g, 17.1 mmol) in acetonitrile (25 ml)under nitrogen at 0° C. Dimethylsulfoxide (3.6 ml, 51.3 mmol) followedby tert-butylammonium bromide (275 mg, 0.85 mmol) were then added andthe reaction was stirred at 0° C. for 2 hours. The mixture was dilutedwith water (100 ml), extracted with diethylether (100 ml) and theorganic phase was washed with brine (50 ml), dried over magnesiumsulphate and concentrated under reduced pressure. The residual pink oilwas purified by flash chromatography on silica gel eluting withcyclohexane:ethyl acetate (80:20, by volume) to provide the titlecompound (3.76 g) as a pink oil.

¹H NMR (400 MHz, CDCl₃): δ=1.17 (t, 3H), 2.62 (q, 2H), 2.96 (t, 2H),3.79 (t, 2H), 4.57 (s, 2H), 7.12 (m, 5H), 15.49 (s, 1H).

LRMS (electrospray): m/z [MNa⁺] 291.

Preparation 603-({(1E)-1-[3-(benzyloxy)propanoyl]-2-hydroxy-1-butenyl}oxy)-5-fluorobenzonitrile

Sodium hydride (60% dispersion in oil, (1.92 g, 48.0 mmol) was added toa stirred solution of the phenol from Preparation 34 (8.80 g, 48.0 mmol)in tetrahydrofuran (450 ml) under nitrogen at room temperature. Afterstirring for 1 hour, the enol from Preparation 59 (12.9 g, 48.0 mmol)was added and the reaction was stirred for 64 hours. The mixture wasdiluted with water (200 ml) and 2N aqueous hydrochloric acid (40 ml),extracted with ethyl acetate (2×150 ml) and the combined organicextracts were washed with brine (100 ml), dried over magnesium sulphateand concentrated under reduced pressure. The residual orange oil waspurified by flash chromatography on silica gel eluting withcyclohexane:pentane (10:90, by volume) to provide the title compound(5.80 g) as an orange oil.

¹H NMR (400 MHz, CDCl₃): δ=1.08 (t, 3H), 2.31 (q, 2H), 2.59 (t, 2H),3.75 (t, 2H), 4.45 (s, 2H), 6.92 (m, 1H), 7.02 (m, 2H), 7.29 (m, 5H),14.50 (s, 1H).

LRMS (electrospray): m/z [MNa⁺] 392.

Preparation 615-({(1E)-1-[3-(Benzyloxy)propanoyl]-2-hydroxy-1-butenyl}oxy)isophthalonitrile

Sodium hydride (60% dispersion in oil, 412 mg, 12.3 mmol) was added to astirred solution of the phenol from Preparation 39 (1.48 g, 10.3 mmol)in tetrahydrofuran (70 ml) under nitrogen at room temperature. Afterstirring for 30 minutes, the enol from Preparation 59 (2.76 g, 10.3mmol) was added and the reaction was stirred for 18 hours. Water (100ml) and 2N aqueous hydrochloric acid (10 ml) were cautiously added andthe mixture extracted with ethyl acetate (2×150 ml). The organics werecombined, washed with brine (100 ml), dried over magnesium sulphate andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica get eluting with (pentane:ethyl acetate90:10, by volume) to provide the title compound (100 g) as a yellow oil.

LRMS (thermospray): m/z [MH⁺] 375.

Preparation 623-{[1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-fluorobenzonitrile

Imidazole (477 mg, 7.02 mmol) and tert-butyl-dimethyl-silyl chloride(977 mg, 6.48 mmol) were sequentially added to a solution of the alcoholfrom Example 117 (1.65 g, 5.40 mmol) in dimethylformamide (11 ml) atroom temperature under nitrogen. The reaction was stirred for 18 hoursand the mixture was diluted with water (100 ml) and extracted withdiethylether (4×50 ml). The combined organic extracts were dried overmagnesium sulphate, concentrated under reduced pressure and the residuewas purified by flash chromatography on silica gel eluting withdichloromethane:methanol (99:1, by volume) to provide the title compound(2.12 g) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=0.03 (s, 6H), 0.84 (s, 9H), 1.10 (m, 6H),2.42 (q, 2H), 2.56 (q, 2H), 4.00 (t, 2H), 4.09 (t, 2H), 6.86 (d, 1H),6.99 (m, 2H).

LRMS (thermospray): m/z [MH⁺] 419.

Microanalysis: Found C, 62.73; H, 7.83; N, 9.75.C₂₂H₃₂FN₃O₂Si.0.06CH₂Cl₂ requires C, 62.68; H, 7.66; N, 9.94%.

Preparation 633-({3,5-Diethyl-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}oxy)-5-fluorobenzonitrile

p-Toluene-sulphonic acid (32 mg, 0.17 mmol) was added to a solution ofthe alcohol from Example 117 (5.04 g, 16.6 mmol) and dihydropyran (7.57ml, 83 mmol) in dichloromethane (65 ml) at room temperature undernitrogen. The reaction was stirred for 2 hours, but starting materialstill remained so a further aliquot of p-toluene-sulphonic acid (284 mg,1.49 mmol) was added and the reaction was stirred for 1 hour. Themixture was diluted with diethylether (90 ml) and washed with a mixedaqueous solution (water (50 ml), brine (25 ml) and saturated aqueoussodium bicarbonate solution (25 ml)). The aqueous phase was extractedwith diethylether (2×60 ml) and the combined organic extracts were driedover magnesium sulphate, concentrated under reduced pressure and theresidue was purified by flash chromatography on silica gel eluting withdichloromethane:methanol (98:2, by volume) to provide the title compound(6.31 g) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.08 (m, 6H), 1.52 (m, 6H), 2.39 (q, 2H),2.54 (q, 2H), 3.45 (m, 1H), 3.64 (m, 1H), 3.75 (m, 1H), 4.06 (m, 1H),4.17 (t, 2H), 4.51 (s, 1H), 6.82 (d, 1H), 7.22 (m, 2H).

LRMS (thermospray): m/z [MH⁺] 388.

Preparation 643-({3,5-Diethyl-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}oxy)-5-fluorobenzamide

Cesium carbonate (269 mg, 0.82 mmol) was added to a solution of3-methyl-3-pyrazolin-5-one (74 mg, 0.75 mmol) in dimethylsulfoxide (1ml) under nitrogen at room temperature and the reaction was stirred for15 minutes. The aryl fluoride from Preparation 63 (291 mg, 0.75 mmol)dissolved in dimethylsulfoxide (1 ml) was then added and the reactionwas heated to 100° C. for 18 hours. After cooling to room temperaturethe reaction was diluted with water (7 ml) and extracted withdiethylether (12 ml). The organic phase was washed with brine (3.5 ml),dried over magnesium sulphate, concentrated under reduced pressure andthe residue was purified by flash chromatography on silica gel elutingwith a solvent gradient of dichloromethane:methanol (99:1 changing to95:5, by volume) to provide the unexpected title compound (108 mg) as anoil.

¹H NMR (400 MHz, CDCl₃): δ=1.12 (m, 6H), 1.56 (m, 6H), 2.44 (q, 2H),2.59 (q, 2H), 3.48 (m, 1H), 3.69 (m, 1H), 3.79 (m, 1H), 4.08 (m, 1H),4.20 (t, 2H), 4.54 (s, 1H), 6.72 (d, 1H), 7.15 (m, 2H).

LRMS (thermospray): m/z [MH⁺] 406.

Microanalysis: Found C, 60.57; H, 6.97; N, 9.97.C₂₁H₂₈FN₃O₄.0.08CH₂Cl₂.0.32H₂O requires C, 60.57; H, 6.94; N, 10.05%.

Preparation 653-({3,5-Diethyl-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}oxy)-5-(1H-pyrazol-1-yl)benzonitrile

Cesium Carbonate (269 mg, 0.82 mmol) was added to a solution of pyrazole(51 mg, 0.75 mmol) in dry dimethylsulfoxide (1 ml) under nitrogen atroom temperature and the reaction was stirred for 15 minutes. The arylfluoride from Preparation 63 (291 mg, 0.75 mmol) dissolved in drydimethylsulfoxide (1 ml) was then added and the reaction was heated to100° C. for 18 hours. After cooling to room temperature the reaction wasdiluted with water (7 ml) and extracted with diethylether (10 ml). Theorganic phase was washed with brine (3 ml), dried over magnesiumsulphate, concentrated under reduced pressure and the residue waspurified by flash chromatography on silica gel eluting with a solventgradient of dichloromethane:methanol (100:0 changing to 90:10, byvolume) to provide the title compound (55 mg).

¹H NMR (400 MHz, CDCl₃): δ=1.13 (m, 6H), 1.58 (m, 6H), 2.44 (q, 2H),2.60 (q, 2H), 3.49 (m, 1H), 3.69 (m, 1H), 3.80 (m, 1H), 4.10 (m, 1H),4.21 (t, 2H), 4.55 (s, 1H), 6.50 (s, 1H), 6.98 (s, 1H), 7.57 (s, 1H),7.63 (s, 1H), 7.72 (s, 1H), 7.89 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 436, [MNa⁺] 458.

HRMS: [MH⁺] Found 436.2352. C₂₄H₃₀N₅O₃ requires 436.2343 [MNa⁺] Found458.2168. C₂₄H₂₉N₅O₃Na requires 458.2162.

Preparations 66-68

The preparation of the following tabulated Preparations of the generalformula

were performed by a similar method to that of Preparation 65 using theappropriate heterocycle as the starting material.

Preparation No. (Starting material preparation no.) R Analytical Data 66(63)

¹H NMR (400 MHz, CDCl₃): δ = 1.13 (m, 6 H), 1.63 (m, 6 H), 2.44 (q, 2H), 2.60 (q, 2 H), 3.46 (m, 1 H), 3.67 (m, 1 H), 3.79 (m, 1 H), 4.08 (m,1 H), 4.20 (t, 2 H), 4.53 (s, 1 H), 6.26 (t, 1 H), 6.64 (d, 1 H), 7.17(s, 1 H), 7.21 (s, 1 H), 7.34 (s, 1 H), 7.41 (t, 1 H). LRMS(thermospray) m/z [MH⁺] 463, [MNa⁺] 485. HRMS: [MH⁺] Found463.2353.C₂₆H₃₁N₄O₄ requires 463.2340 [MNa⁺] Found 485.2166.C₂₆H₃₀N₄O₄Na requires 485.2159. 67 (63)

¹H NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6 H), 1.56 (m, 6 H), 2.41 (q, 2H), 2.56 (q, 2 H), 3.44 (m, 1 H), 3.64 (m, 1 H), 3.75 (m, 1 H), 4.05 (m,1 H), 4.17 (t, 2 H), 4.50 (s, 1 H), 7.00 (d, 1 H), 7.08 (s, 1 H), 7.20(m, 1 H), 7.51 (s, 1 H), 7.64 (s, 1 H), 7.86 (s, 1 H). LRMS(thermospray): m/z [MH⁺] 464, [MNa⁺] 486. HRMS: [MH⁺] Found 464.2297.C₂₅H₃₀N₅O₄ requires 464.2293 [MNa⁺] Found 486.2113. C₂₅H₃₀N₅O₄Narequires 486.2112. 68¹(63)

¹NMR (400 MHz, CDCl₃): δ = 1.08 (m, 6 H), 1.48 (m, 6 H), 2.23 (s, 3 H),2.38 (q, 2 H), 2.53 (q, 2 H), 3.43 (m, 1 H), 3.63 (m, 1 H), 3.66 (s, 3H), 3.73 (m, 1 H), 4.04 (m, 1 H), 4.15 (t, 2 H), 4.50 (s, 1 H), 5.59 (s,1 H), 6.76 (s, 1 H), 6.88 (s, 1 H), 6.95 (s, 1 H). LRMS (thermospray):m/z [MH⁺] 480, [MNa⁺] 502. ¹The eluent used for flash columnchromatography purification of this compound was dichloromethane:methanol (99:1 changing to 95:5, by volume).

Preparation 69 tert-Butyl3-[4-(3,5-dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-1-azetidinecarboxylate

Sodium hydride (60% dispersion in oil, 33 mg, 0.82 mmol) was added to asolution of the pyrazole from Example 122 (200 mg, 0.75 mmol) indimethylformamide (3 ml) at 0° C. under nitrogen and the reaction wasstirred for 10 minutes. 3-Iodo-azetidine-1-carboxylic acid tert-butylester (234 mg, 0.82 mmol) was added and the reaction was stirred at roomtemperature for 18 hours. The reaction was quenched with water (0.2 ml)and concentrated under reduced pressure. The residue was partitionedbetween dichloromethane (5 ml) and water (5 ml) and the organic phasewas isolated using a 5 μM Whatman PTFE fritted cartridge, thenconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with a solvent gradient of ethylacetate:pentane (20:80 then 25:75 then 34:66 then 50:50 then 75:25 then100:0, by volume) changing to ethyl acetate:methanol (10:1, by volume)then dichloromethane:methanol:0.88 ammonia (90:10:1 then 80:20:1, byvolume) to provide the title compound (189 mg) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=1.03-1.17 (m, 6H), 1.49 (s, 9H), 2.39-2.52(m, 4H), 4.32 (m, 2H), 4.50 (m, 2H), 4.94 (m, 1H), 7.38 (s, 2H), 7.56(s, 1H).

LRMS (thermospray): m/z [MH⁺] 422, [MNa⁺] 444.

Microanalysis: Found C, 65.08; H, 6.49; N, 16.48. C₂₃H₂₇N₅O₃.0.18H₂Orequires C, 65.04; H, 6.49; N, 16.49%.

Preparation 705-({3,5-Diethyl-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-1H-pyrazol-4-yl}oxy)isophthalonitrile

Sodium hydride (60% dispersion in oil, 33 mg, 0.82 mmol) was added to asolution of the pyrazole from Example 122 (200 mg, 0.75 mmol) indimethylformamide (3 ml) at 0° C. under nitrogen and the reaction wasstirred for 10 minutes. 2-(3-bromo-propoxy)-tetrahydro-pyran (184 mg,0.82 mmol) was added and the reaction was stirred at room temperaturefor 18 hours. The reaction was quenched with water (0.2 ml) andconcentrated under reduced pressure. The residue was partitioned betweendichloromethane (5 ml) and water (5 ml) and the organic phase wasisolated using a 5 μM Whatman PTFE fritted cartridge, then concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with a solvent gradient of ethyl acetate:pentane(20:80 then 25:75 then 34:66 then 50:50 then 75:25 then 100:0, byvolume) changing to ethyl acetate:methanol (10:1, by volume) thendichloromethane:methanol:0.88 ammonia (90:10:1 then 80:20:1, by volume)to provide the title compound (238 mg) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=1.09 (m, 6H), 1.47-1.63 (m, 2H), 1.66-1.88(m, 2H), 2.15 (dd, 2H), 2.38 (q, 2H), 2.53 (q, 2H), 3.37-3.55 (m, 2H),3.75-3.90 (m, 2H), 4.11 (m, 2H), 4.56 (m, 1H), 7.37 (s, 2H), 7.55 (s,1H).

LRMS (electro): m/z [MH⁺] 409, [MNa⁺] 421.

Microanalysis: Found C, 66.59; H, 6.91; N, 13.40. C₂₃H₂₈N₄O₃.0.36H₂Orequires C, 66.57; H, 6.98; N, 13.50%.

Preparation 713-[(1-Acetyl-3,5-dimethyl-1H-pyrazol-4-yl)oxy]-5-fluorobenzonitrile

The phenol from Preparation 34 (10.0 g, 72.7 mmol),3-chloro-2,4-pentanedione (7.10 g, 72.7 mmol) and cesium carbonate (23.6g, 72.9 mmol) were heated to reflux in acetone (100 ml) under nitrogenfor 2 hours. The reaction was cooled to room temperature, 1N aqueoushydrochloric acid (50 ml) was added slowly and the mixture was extractedwith ethyl acetate (3×100 ml). The combined organic extracts dried overmagnesium sulphate and concentrated under reduced pressure. The residualyellow oil was dissolved in methanol (100 ml), hydrazine (5.3 ml, 109mmol) was added and the reaction was stirred at room temperature undernitrogen for 2 hours. The solvent was removed under reduced pressure andthe residue was dissolved in dimethylformamide (50 ml) at 0° C. Acetylchloride (5.1 ml, 72.0 mmol) was added slowly followed by sodium hydride(60% dispersion in oil, 2.8 g, 72.0 mmol) portionwise. The reaction wasstirred for 15 minutes and sat. ammonium chloride solution (50 ml) wasadded, and the reaction was allowed to warm to room temperature. Themixture was extracted with ethyl acetate (3×100 ml) and the combinedorganic extracts were dried over magnesium sulphate and concentratedunder reduced pressure giving an oil. After standing for 18 hours, asolid had formed within the oil which was isolated by filtration,washing with diethylether (50 ml) to provide the title compound (3.50 g)as a white solid, m.p. 109-111° C.

¹H NMR (400 MHz, CDCl₃): δ=2.06 (s, 3H), 2.37 (s, 3H), 2.65 (s, 3H),6.81 (d, 1H), 6.91 (s, 1H), 7.04 (d, 1H).

LRMS (thermospray): m/z [MH⁺] 273.

Microanalysis: Found C, 61.62; H, 4.44; N, 15.09. C₁₄H₁₂N₃O₂F requiresC, 61.53; H, 4.43; N, 15.38%.

Preparations 72-74

The tabulated compounds of the general formula

were performed by a similar method to that of Preparation 71 using theappropriate phenol as the starting material.

Preparation no. (Starting material preparation no.) R′ Analytical Data 72 (39) CN m.p. 204-206° C. ¹H NMR (400 MHz, CDCl₃): δ = 2.06 (s, 3H),2.38 (s, 3H), 2.66 (s, 3H), 7.33 (s, 2H), 7.58 (s, 1H). LRMS(thermospray): m/z [MH⁺] 281. Microanalysis: Found C, 63.30; H, 4.25; N,19.59. C₁₅H₁₂N₄O₂•0.30H₂O requires C, 63.06; H, 4.45; N, 19.61%. 73¹(42) Me m.p. 152-154° C. ¹H NMR (400 MHz, CDCl₃): δ = 2.05 (s, 3H), 2.33(s, 3H), 2.38 (s, 3H), 2.66 (s, 3H), 6.88 (s, 1H), 6.91 (s, 1H), 7.12(s, 1H). LRMS (thermospray): m/z [MH⁺] 270. Microanalysis: Found C,66.67; H, 5.71; N, 15.25. C₁₅H₁₅N₃O₂ requires C, 66.9; H, 5.61; N,15.60%. 74² (Commercial) H m.p. 131-133° C. ¹H NMR (400 MHz, CDCl₃): δ =2.13 (s, 3H), 2.40 (s, 3H), 2.70 (s, 3H), 7.15 (m, 2H), 7.35 (m, 1H),7.40 (m, 1H). LRMS (thermospray): m/z [MH⁺] 278. Microanalysis: Found C,65.87; H, 5.11; N, 16.33. C₁₄H₁₃N₃O₂ requires C, 65.87; H, 5.13; N,14.46%. ¹The product was purified by flash column chromatography onsilica gel eluting with ethyl acetate:pentane (10:90, by volume). ²Theproduct was purified by flash column chromatography on silica geleluting with ethyl acetate:pentane (10:90, changing to 20:80, by volume)

Preparation 753-{[1-Acetyl-3-(bromomethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-5-fluorobenzonitrile

The pyrazole from Preparation 71 (1.00 g, 3.66 mmol) was dissolved incarbon tetrachloride (20 ml) and the solution was degassed by bubblingnitrogen through it for 20 minutes at room temperature.N-Bromosuccinimide (973 mg, 5.49 mmol) followed by2,2′-azobisisobutyronitrile (30 mg) were added and the reaction washeated to 95° C. for 1 hour. The reaction was cooled to roomtemperature, concentrated under reduced pressure and purified by flashchromatography on silica gel eluting with pentane:ethyl acetate (80:20,by volume) to provide the title compound (1.30 g) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=2.05 (s, 3H), 2.69 (s, 3H), 4.68 (s, 2H),6.89 (d, 1H), 6.99 (s, 1H), 7.08 (d, 1H).

LRMS (thermospray): m/z [M-BrH⁺] 272.

Microanalysis: Found C, 45.08; H, 3.14; N, 11.44. C₁₄H₁₁BrN₃O₂F.1.05H₂Orequires C, 45.31; H, 3.56; N, 11.32%.

Preparations 76-78

The preparation of the following tabulated Preparations of the generalformula

were performed by a similar method to that of Preparation 75 using theappropriate pyrazole as the starting material.

Preparation no. (Starting material preparation no.) R Analytical Data  76 (72) CN m.p. 132-134° C. ¹H NMR (400 MHz, CDCl₃): δ = 2.06 (s, 3H),2.66 (s, 3H), 4.67 (s, 2H), 7.40 (s, 2H), 7.63 (s, 1H). Microanalysis:Found C, 47.65; H, 3.03; N, 14.79. C₁₅H₁₁BrN₄O₂•0.93H₂O requires C,47.92; H, 3.45; N, 14.90%. 77^(1,2) (73) Me m.p. 107-109° C. ¹H NMR (400MHz, CDCl₃): δ = 2.05 (s, 3H), 2.35 (s, 3H), 2.70 (s, 3H), 4.70 (s, 2H),6.95 (s, 1H), 6.99 (s, 1H), 7.18 (s, 1H). Microanalysis: Found C, 50.34;H, 3.89; N, 11.58. C₁₅H₁₄BrN₃O₂•0.40H₂O requires C, 50.69; H, 4.20; N,11.82%. 78^(1,3) (74) H m.p. 120-124° C. ¹H NMR (400 MHz, CDCl₃): δ =2.05 (s, 3H), 2.70 (s, 3H), 4.75 (s, 2H), 7.20 (m, 2H), 7.45 (m, 1H).Microanalysis: Found C, 49.01; H, 3.47; N, 12.14. C₁₄H₁₂BrN₃O₂•0.50H₂Orequires C, 49.00; H, 3.82; N, 12.24%. ¹A further aliquot of2,2′-azobisisobutyronitrile (30 mg) was added to this reaction, andrefluxing was continued for a further 2 hours. ²The product was purifiedby flash column chromatography on silica gel eluting with a solventgradient of ethyl acetate:pentane (0:100 then 2:98 then 5:95 then 10:90then 15:85 then 30:70, by volume). ³The product was purified by flashcolumn chromatography on silica gel eluting with ethyl acetate:pentane(10:90 changing to 20:80, by volume).

Preparation 79 3-Cyanobenzamide

0.88 Ammonia solution (30 ml) was slowly added to a solution of3-cyanobenzoyl chloride (10 g, 60.3 mmol) in dichloromethane (100 ml) at0° C. under nitrogen and the reaction was stirred for 20 minutes. Themixture was filtered and the solid was washed with water (50 ml) thendiethylether (50 ml), azeotroped with toluene and dried in vacuo toprovide the title compound (9 g) as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.62 (m, 1H), 7.86 (m, 1H), 8.12 (m, 1H),8.18 (s, 1H).

Preparation 80 3-(Aminomethyl)benzamide

The nitrile from Preparation 79 (6.4 g, 43.8 mmol) was suspended inacetic acid (60 ml) and 10% palladium on carbon (100 mg) was added. Thereaction was pressurised to 60 psi at room temperature with hydrogen,and stirred for 18 hours. Starting material remained, so a furtheraliquot of 10% palladium on carbon (500 mg) was added and the procedurewas repeated. The reaction mixture was filtered through arbocel washingwith acetic acid and the filtrate was concentrated under reducedpressure. The residue was azeotroped with toluene and purified by flashchromatography on silica gel eluting with dichloromethane:methanol:0.88ammonia (100:0:0 changing to 90:10:1 then 85:15:1.5, by volume) toprovide the title compound (5.3 g) as a colourless oil.

¹H NMR (400 MHz, CD₃OD): δ=3.83 (s, 2H), 7.39 (dd, 1H), 7.49 (d, 1H),7.73 (d, 1H), 7.81 (s, 1H).

Preparation 81 2-Chloro-1,3-dicyclopropyl-1,3-propanedione

Trimethylsilyl chloride (16.6 ml, 130 mmol) was added to a solution oftert-butylammonium bromide (0.70 g, 2.17 mmol) in acetonitrile (50 ml)under nitrogen at 0° C. 1,3-Dicyclopropyl-propane-1,3-dione (ref:WO98155438) (6.62 g, 43.5 mmol) in acetonitrile (15 ml) was then addedfollowed by dimethylsulfoxide (9.25 ml, 130 mmol) dropwise, and thereaction was allowed to warm to room temperature over 4 hours. Themixture was diluted with water (75 ml), extracted with diethylether(3×35 ml) and the combined organic extracts dried over magnesiumsulphate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withpentane:diethylether (95:5, by volume) to provide the title compound(3.76 g) as an oil, which was an 80:20 mixture of enol:keto forms.

¹H NMR (400 MHz, CDCl₃): δ=1.02 (m, 4H), 1.17 (m, 4H), 2.24 (m, 0.2H),2.39 (m, 0.8H), 5.05 (s, 0.2H), 16.34 (s, 0.8H).

Microanalysis: Found C, 57.59; H, 5.89. C₉H₁₁ClO₂.0.02CH₂Cl₂ requires C,57.92; H, 5.94.

Preparation 825-[2-Cyclopropyl-1-(cyclopropylcarbonyl)-2-oxoethoxy]isophthalonitrile

Cesium carbonate (1.97 g, 6.06 mmol) was added to a stirred solution ofthe phenol from Preparation 39 (0.865 g, 6.00 mmol) in acetone (24 ml)under nitrogen at reflux. After stirring for 5 minutes, the diketonefrom Preparation 81 (1.12 g, 6.00 mmol) in acetone (6 ml) was added andthe reaction was stirred for 4 hours. After cooling the mixture wasdiluted with water (25 ml) and the acetone was removed under reducedpressure. The aqueous phase was acidified with 2N aqueous hydrochloricacid, extracted with dichloromethane (50 ml) and the organic phase wasdried over magnesium sulphate and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith a solvent gradient of pentane:ethyl acetate (95:5 changing to 90:10then 80:20, by volume) to provide the title compound (1.03 g) as a whitesolid, which existed as the enol tautomer, m.p. 135-137° C.

¹H NMR (400 MHz, CDCl₃): δ=0.93 (m, 4H), 1.19 (m, 4H), 1.74 (m, 2H),7.53 (s, 2H), 15.25 (s, 1H).

LRMS (electrospray): m/z [M-H⁺] 293.

Microanalysis: Found C, 69.18; H, 4.82; N, 9.35. C₁₇H₁₄N₂O₃ requires C,69.38; H, 4.79; N, 9.52%.

Preparation 83 3-Oxobutanoic acid

Sodium hydroxide (37.9 g, 0.947 mol) was dissolved in water (770 ml) andadded to a solution of 3-oxo-butanoic acid methyl ester (100 g, 0.861mol) at room temperature over 20 minutes. The reaction was stirred for18 hours, quenched with ammonium sulfate (700 g) and acidified slowlywith a solution of concentrated Hydrochloric acid (21.5 ml) in water(250 ml) with ice cooling. The reaction mixture was extracted withdiethylether (6×200 ml) and the combined organic extracts were driedover magnesium sulphate and concentrated under reduced pressure toprovide the title compound (58.2 g) as a pale yellow oil which was amixture of keto:enol tautomers.

¹H NMR (400 MHz, CDCl₃): δ=2.00 (s, 3H-enol), 2.30 (s, 3H-keto), 3.51(s, 2H-keto), 5.02 (s, 1H-enol).

Preparation 84 1-Cyclopropyl-1,3-butanedione

Magnesium turnings (3.04 g, 125 mmol) suspended in methanol (145 ml)were heated to reflux under nitrogen for 1 hour, cooled to roomtemperature and the β-keto acid from Preparation 83 (25.5 g, 250 mmol)dissolved in methanol (25 ml) was added dropwise with ice-cooling. Thereaction was stirred for 1 hour at room temperature and the solvent wasremoved under reduced pressure to give the magnesium salt of the acid.Meanwhile, cyclopropane-carboxylic acid (9.91 ml, 125 mmol) wasdissolved in dimethylformamide (200 ml) and carbonyldiimidazole (22.4 g,138 mmol) was added portionwise under nitrogen at 0° C. This was stirredfor 1.5 hour and the magnesium salt from above was added as a solutionin dimethylformamide (100 ml) at 0° C. The reaction was allowed to stirat room temperature for 92 hours and the mixture was poured into 2Maqueous hydrochloric acid (85 ml) then diluted with water (170 ml). Themixture was extracted with diethylether (6×200 ml) and the combinedorganic extracts were washed with brine (3×200 ml), dried over magnesiumsulphate and concentrated under reduced pressure. The residual orangeoil was purified by flash chromatography on silica gel eluting withpentane:diethylether (100:0 changing to 90:10 then 80:20, by volume) toprovide the title compound (7.39 g) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=0.83-0.95 (m, 2H), 1.06-1.10 (m, 2H),1.54-1.63 (m, 1H), 2.00 (s, 3H).

LRMS (electrospray): m/z [MNa⁺] 149.

Preparation 85 2-Chloro-1-cyclopropyl-1,3-butanedione

Trimethylsilyl chloride (18.9 ml, 174 mmol) was added to a solution oftert-butylammonium bromide (932 mg, 2.89 mmol) in dry acetonitrile (50ml) under nitrogen at room temperature and the mixture was cooled to 0°C. The diketone from Preparation 84 (7.3 g, 57.9 mmol) in acetonitrile(36 ml) was then added followed by dropwise addition of drydimethylsulfoxide (12.3 ml, 174 mmol). The reaction was stirred at 0° C.for 1.5 hours and the mixture was diluted with water (500 ml), extractedwith diethylether (2×200 ml and 100 ml) and the combined organicextracts were dried over magnesium sulphate and concentrated underreduced pressure. The residual oil was purified by flash chromatographyon silica gel eluting with pentane:diethylether (100:0 changing to 95:5then 90:10, by volume) to provide the title compound (5.76 g) as acolourless oil.

¹H NMR (400 MHz, CDCl₃): δ=0.99-1.08 (m, 2H), 1.15-1.20 (m, 2H), 2.27(s, 3H), 2.38-2.46 (m, 1H),

LRMS (electrospray): m/z [M-H⁺] 159.

Preparation 863-[1-(Cyclopropylcarbonyl)-2-oxopropoxy]-5-methylbenzonitrile

Cesium carbonate (2.45 g, 8.30 mmol) and the phenol from Preparation 42(1 g, 7.50 mmol) were added to a stirred solution of the diketone fromPreparation 85 (1.3 g, 8.30 mmol) in acetone (44 ml) under nitrogen at60° C. and the reaction was stirred for 5 hours. After cooling themixture was quenched with water and the acetone was removed underreduced pressure. The aqueous phase was acidified with 1N aqueoushydrochloric acid, extracted with ethyl acetate and the organic phasewas dried over magnesium sulphate and concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with pentane:ethyl acetate (85:15, by volume) to provide thetitle compound (1.03 g) as a pale red solid.

¹H NMR (400 MHz, CDCl₃): δ=0.85 (m, 2H), 1.12 (m, 2H), 1.86 (m, 1H),1.94 (s, 3H), 2.35 (s, 3H), 6.99 (m, 2H), 7.10 (s, 1H).

LRMS (electrospray): m/z [M-H⁺] 256.

Preparation 874-(3,5-Difluorophenoxy)-3,5-diethyl-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazole

p-Toluene-sulphonic acid (360 mg, 1.89 mmol) was added to a solution ofthe alcohol from Example 38 (5.6 g, 18.9 mmol) and dihydropyran (8.62ml, 94.5 mmol) in dichloromethane (75 ml) at room temperature undernitrogen. The reaction was stirred for 2 hours, diluted withdiethylether (100 ml) and washed with a mixed aqueous solution (water(60 ml), brine (30 ml) and saturated aqueous sodium bicarbonate solution(30 ml)). The aqueous phase was extracted with diethylether (2×60 ml)and the combined organic extracts were dried over magnesium sulphate,concentrated under reduced pressure and the residue was purified byflash chromatography on silica gel eluting with dichloromethane:methanol(98:2, by volume) to provide the title compound (6.31 g) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.09 (m, 6H), 1.57 (m, 6H), 2.40 (q, 2H),2.55 (q, 2H), 3.44 (m, 1H), 3.62 (m, 1H), 3.73 (m, 1H), 4.05 (m, 1H),4.16 (t, 2H), 4.50 (s, 1H), 6.39 (m, 3H).

LRMS (thermospray): m/z [MH⁺] 381.

Microanalysis: Found C, 62.16; H, 6.92; N, 7.16. C₂₀H₂₆N₂O₃.0.09CH₂Cl₂requires C, 62.18; H, 6.80; N, 7.22%.

Preparation 884-[3,5-Di(1H-pyrazol-1-yl)phenoxy]-3,5-diethyl-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazole

and

Preparation 893,5-Diethyl-4-[3-fluoro-5-(1H-pyrazol-1-yl)phenoxy]-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazole

Cesium Carbonate (538 mg, 1.65 mmol) was added to a solution of pyrazole(102 mg, 1.50 mmol) in dry dimethylsulfoxide (2 ml) under nitrogen atroom temperature and the reaction was stirred for 15 minutes. The aryldifluoride from Preparation 87 (570 mg, 1.50 mmol) dissolved in drydimethylsulfoxide (2 ml) was then added and the reaction was heated to100° C. for 18 hours. After cooling to room temperature the reaction wasdiluted with water (20 ml) and extracted with diethylether (2×20 ml).The organic phase was washed with brine (10 ml), dried over magnesiumsulphate, concentrated under reduced pressure. Some starting materialremained, so the residue was dissolved in dimethylsulfoxide (12 ml),pyrazole (510 mg, 7.50 mmol) followed by cesium carbonate (2.5 g, 7.66mmol) were added and the reaction was heated to 100° C. for 18 hours.After cooling to room temperature the reaction was diluted with water (6ml), extracted with diethylether (20 ml) and the organic phase waswashed with brine (10 ml), dried over magnesium sulphate, concentratedunder reduced pressure and the residue was purified by flashchromatography on silica gel eluting with a solvent gradient ofdichloromethane:methanol (100:0 changing to 96:4, by volume). This gavetwo fractions, the first of which was a single product (least polar) andthe other a mixture of two products. The second fraction was re-purifiedeluting with dichloromethane:acetonitrile (93:7 changing to 90:10, byvolume) to provide the most polar product.

Least Polar Product—Preparation 88 (254 mg)

¹H NMR (400 MHz, CDCl₃): δ=1.11 (m, 6H), 1.50 (m, 6H), 2.46 (q, 2H),2.58 (q, 2H), 3.43 (m, 1H), 3.64 (m, 1H), 3.75 (m, 1H), 4.04 (m, 1H),4.18 (t, 2H), 4.50 (s, 1H), 6.42 (s, 2H), 7.15 (s, 2H), 7.67 (s, 3H),7.90 (s, 2H).

LRMS (electrospray): m/z [MH⁺] 477, [MNa⁺] 499.

HRMS: [MH⁺] Found 477.2612. C₂₆H₃₃N₆O₃ requires 477.2609.

Most Polar Product—Preparation 89 (37.7 mg)

¹H NMR (400 MHz, CDCl₃): δ=1.11 (m, 6H), 1.46 (m, 6H), 2.43 (q, 2H),2.57 (q, 2H), 3.43 (m, 1H), 3.64 (m, 1H), 3.75 (m, 1H), 4.05 (m, 1H),4.17 (t, 2H), 4.51 (s, 1H), 6.42 (m, 2H), 7.07 (m, 2H), 7.66 (s, 1H),7.82 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 429.

Preparation 903-({3,5-Diethyl-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}oxy)-5-methoxybenzonitrile

Sodium methoxide (25% w/v in methanol, 230 μl, 1.00 mmol) was addeddropwise to a solution of the aryl fluoride from Preparation 63 (387 mg,1.00 mmol) and in dimethylformamide (5 ml) at room temperature undernitrogen. The reaction was stirred for 5 hours, diluted with water (10ml) and extracted with diethylether (50 ml). The organic phase was driedover magnesium sulphate, concentrated under reduced pressure and theresidue was purified by flash chromatography on silica gel eluting withdichloromethane:methanol (97:3, by volume) to provide the title compound(400 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.09 (m, 6H), 1.49 (m, 6H), 2.41 (q, 2H),2.55 (q, 2H), 3.46 (m, 1H), 3.66 (m, 1H), 3.77 (m+s, 4H), 4.07 (m, 1H),4.19 (t, 2H), 4.52 (m, 1H), 6.66 (s, 1H), 6.69 (s, 1H), 6.77 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 400.

Microanalysis: Found C, 65.59; H, 7.32; N, 10.42. C₂₂H₂₉N₃O₄.0.04CH₂Cl₂requires C, 65.71; H, 7.28; N, 10.43%.

Preparation 91 3-(1-Acetyl-3-methyl-2-oxobutoxy)-5-methylbenzonitrile

Cesium carbonate (1.50 g, 4.61 mmol) and the phenol from Preparation 42(609 mg, 4.61 mmol) were added to a stirred solution of the diketonefrom Preparation 23 (750 mg, 4.61 mmol) in acetone (23 ml) undernitrogen at 50° C. and the reaction was stirred for 3 hours. Aftercooling the mixture was quenched with water (10 ml) and the acetone wasremoved under reduced pressure. The aqueous phase was extracted withdichloromethane (4×25 ml) and the combined organic extracts were driedover magnesium sulphate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withpentane:ethyl acetate (90:10, by volume) to provide the title compound(544 mg).

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.09 (s, 3H), 2.42 (s, 3H),2.69 (m, 1H), 7.00 (s, 2H), 7.19 (s, 1H).

LRMS (thermospray): m/z[MNH₄ ⁺] 277.

Preparation 92 [4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]aceticacid

The pyrazole of Example 208 (400 mg, 1.41 mmol) was stirred at 100° C.for 14 hours in concentrated hydrochloric acid (20 ml). The mixture wascooled to room temperature and the solvent removed under reducedpressure to give a yellow solid. The solid was dissolved indichloromethane (50 ml) and 1N aqueous hydrochloric acid (50 ml) and theorganic layer was separated. The organics were washed with 1N aqueoushydrochloric acid (50 ml), dried over magnesium sulphate, filtered andthe solvent removed under reduced pressure to provide the title compound(400 mg) as pale yellow solid, m.p. 156-158° C.

¹H NMR (400 MHz, CD₃OD): δ=2.02 (s, 3H), 4.89 (s, 2H), 6.82 (s, 2H),7.02 (s, 1H).

LRMS (thermospray): m/z [MH⁺] 303.

Microanalysis: Found C, 47.50; H, 3.50; N, 9.46. C₁₂H₁₀Cl₂N₂O₃ requiresC, 47.86; H, 3.35; N, 9.30%.

Preparation 933-({3,5-Diethyl-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}oxy)-5-(methylsulfanyl)benzonitrile

Sodium thiomethoxide (180 mg, 2 mmol) was added to a stirred solution ofthe aryl fluoride from Preparation 63 (774 mg, 2.00 mmol) indimethylformamide (10 ml) at room temperature under nitrogen. Thereaction mixture was stirred for 5 hours before being heated at 100° C.for 18 hours. A second portion of sodium thiomethoxide (90 mg, 1 mmol)was added and the reaction mixture was heated at 100° C. for a further 5hours. After cooling to room temperature the mixture was diluted withwater (10 ml) and extracted with diethylether (2×50 ml). The organicphase was dried over magnesium sulphate, concentrated under reducedpressure and the residue was purified by flash chromatography on silicagel eluting with dichloromethane:methanol (97:3, by volume) to providethe title compound (700 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.14 (m, 6H), 1.52 (m, 6H), 2.44 (q, 2H),2.49 (s, 3H), 2.59 (q, 3H), 3.50 (m, 1H), 3.70 (m, 1H), 3.80 (m, 1H),4.10 (m, 1H), 4.23 (m, 2H), 4.55 (m, 1H), 6.82 (s, 1H), 7.01 (s, 1H),7.09 (s, 1H).

LRMS (APCl+): m/z [MH⁺] 416.

Preparation 943-({3,5-Diethyl-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}oxy)-5-[2-(dimethylamino)ethoxy]benzonitrile

To a stirred solution of N,N-dimethylethanolamine (83 μl, 0.83 mmol) indimethylformamide (2 ml) was added sodium hydride (36 mg of 60% byweight dispersion in oil, 0.90 mmol). After 10 minutes a solution of thearyl fluoride from Preparation 63 (291 mg, 0.75 mmol) indimethylformamide (2 ml) was added and the reaction mixture was stirredat room temperature for 18 hours. The mixture was diluted with 10%aqueous potassium carbonate solution (12 ml) and extracted with diethylether (2×7 ml). The combined organic components were dried overmagnesium sulphate and concentrated under reduced pressure. The crudeproduct mixture was purified by flash chromatography on silica geleluting with dichloromethane:methanol (a gradient from 99:1 to 90:10, byvolume) to provide the title compound (180 mg) as an oil.

¹H NMR (400 MHz, CDCl₃): δ=1.09 (m, 6H), 1.50 (m, 6H), 2.39 (q, 2H),2.47 (s, 6H), 2.55 (q, 2H), 2.87 (m, 2H), 3.47 (m, 1H), 3.67 (m, 1H),3.78 (m, 1H), 4.05 (m, 1H), 4.17 (m, 4H), 4.52 (m, 1H), 6.70 (s, 2H),6.79 (s, 1H).

LRMS (electrospray): m/z [MH⁺] 457.

HRMS: [MH⁺] 457.2810. C₂₅H₃₇N₄O₄ requires 457.2810.

Preparations 95-97

The preparation of the following tabulated Preparations of the generalformula

were performed by a similar method to that of Preparation 94 using theappropriate alcohol as the starting material.

Preparation no. (Starting material preparation no) R Analytical Data 95(63) CH₂CH₂ NHMe ¹H NMR (400 MHz, CDCl₃): δ = 1.09 (m, 6H), 1.50 (m,6H), 2.39 (q, 2H), 2.54 (m, 5H), 3.04 (t, 2H), 3.46 (m, 1H), 3.66 (m,1H), 3.78 (m, 1H), 4.05 (m, 1H), 4.11 (t, 2H), 4.17 (t, 2H), 4.52 (s,1H), 6.70 (s, 2H), 6.81 (s, 1H). LRMS (electrospray): m/z [MH⁺] 443HRMS: [MH⁺] 443.2654. C₂₄H₃₅N₄O₄ requires 443.2653. 96 (63) CH₂CONH₂ ¹HNMR (400 MHz, CDCl₃): δ = 1.11 (m, 6H), 1.48 (m, 6H), 2.43 (q, 2H), 2.58(q, 2H), 3.46 (m, 1H), 3.67 (m, 1H), 3.80 (m, 1H), 4.08 (m, 1H), 4.25(m, 2H), 4.45 (s, 2H), 4.52 (m, 1H), 5.54 (broad s, 1H), 6.37 (broad s,1H), 6.72 (s, 1H), 6.85 (s, 2H). LRMS (electrospray): m/z 465 (MH⁺)HRMS: [MH⁺] 443.2282. C₂₃H₃₁N₄O₅ requires 443.2289. 97 (63) CH₂CH₂OCH₃¹H NMR (400 MHz, CDCl₃): δ = 1.10 (m, 6H), 1.50 (m, 6H), 2.41 (q, 2H),2.55 (q, 2H), 3.41 (s, 3H), 3.47 (m, 1H), 3.70 (m, 3H), 3.79 (m, 1H),4.06 (m, 3H), 4.20 (m, 2H), 4.52 (s, 1H), 6.70 (s, 2H), 6.79 (s, 1H).LRMS (electrospray): m/z 466 (MH⁺) HRMS: [MH⁺] 443.2282. C₂₄H₃₄N₃O₅requires 443.2289.

Preparation 98 5-Methyl-1-[2-(tetrahydro-2pyran-2-yloxy)ethyl]-3-(trifluoromethyl)-1H-pyrazol-4-ol

To a stirred solution of1-(2-hydroxyethyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ol (600 mg,2.86 mmol; Kenkyu Hokoku—Asahi Garasu Kogyo Gijutsu Shoreikai 1988, 51,139-49) in dichloromethane (10 ml) and ethyl acetate (4 ml) was addedpara-toluenesulphonic acid (27 mg, 0.14 mmol) followed by3,4-dihydro-2H-pyran (340 μl, 3.7 mmol). The reaction mixture wasstirred at room temperature for 3 hours before being concentrated underreduced pressure. The crude product mixture was purified by flashchromatography on silica gel eluting with pentane:ethyl acetate (60:40,by volume) to provide the title compound (560 mg) as white solid.

¹H NMR (400 MHz, CDCl₃): δ=1.60 (m, 6H), 2.23 (s, 3H), 3.44 (m, 1H),3.60 (m, 1H), 3.72 (m, 1H), 4.04 (m, 1H), 4.18 (m, 2H), 4.50 (broad s,1H).

LRMS (electrospray): m/z [M-H⁺] 293.

Preparation 993-Fluoro-5-{[5-methyl-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl]oxy}benzonitrile

To a stirred solution of the pyrazole (214 mg, 0.73 mmol) fromPreparation 98 in dimethylformamide (0.7 ml) was added3,5-difluorobenzonitrile (304 mg, 2.2 mmol) and potassium carbonate (304mg, 2.2 mmol). The reaction mixture was heated at 90° C. for 7 hours.After cooling to room temperature brine (20 ml) was added and themixture was extracted with ethyl acetate (20 ml). The organic componentwas separated, washed with brine (20 ml), dried over magnesium sulphateand concentrated under reduced pressure. The crude product mixture waspurified by flash chromatography on silica gel eluting withpentane:ethyl acetate (80:20, by volume) to provide the title compound(267 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.61 (m, 6H), 2.18 (s, 3H), 3.48 (m, 1H),3.64 (m, 1H), 3.75 (m, 1H), 4.30 (t, 2H), 4.50 (broad s, 1H), 6.85 (d,1H), 6.94 (s, 1H), 7.05 (d, 1H).

LRMS (electrospray): m/z [M-H⁺] 412.

Preparation 1003-Cyano-5-[(3,5-diethyl-1-{2-[(2-methoxyethoxy)methoxy]ethyl}-1H-pyrazol-4-yl)oxy]benzamide

To a stirred solution of the pyrazole from Example 261 (193 mg, 0.49mmol) in tetrahydrofuran (2 ml) was added 2M aqueous sodium hydroxidesolution (8.7 μl, 0.49 mmol) and the reaction mixture was heated at 65°C. for 24 hours. After cooling to room temperature a second portion of2M sodium hydroxide solution (8.7 μl, 0.49 mmol) was added and themixture was heated at 65° C. for 24 hours. 6M aqueous sodium hydroxidesolution (100 μl) was added and the mixture was heated at 65° C. for 24hours. The reaction mixture was concentrated under reduced pressure,diluted with water (75 ml), neutralised to pH7 using 2M aqueoushydrochloric acid solution and extracted with dichloromethane (2×25 ml).The combined organic components were dried over magnesium sulphate andconcentrated under reduced pressure to give a crude product mixturewhich was purified by flash chromatography on silica gel eluting withdichloromethane:methanol (100:0, 98:2, 96.5:3.5 then 95:5, by volume) toprovide the title compound (60 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.10 (m, 6H), 2.40 (q, 2H), 2.55 (q, 2H),3.36 (s, 3H), 3.50 (q, 2H), 3.59 (q, 2H), 3.94 (q, 2H), 4.20 (q, 2H),4.64 (s, 2H), 7.30 (s, 1H), 7.59 (s, 1H), 7.70 (s, 1H).

Preparation 1015-[(1-Acetyl-3,5-diethyl-1H-pyrazol-4-yl)oxy]isophthalonitrile

To a stirred solution of the pyrazole from Example 122 (3.0 g, 11.3mmol) in dimethylformamide (45 ml) at 0° C. was added acetyl chloride(1.2 ml, 17.0 mmol), followed by sodium hydride portionwise (678 mg of60% by weight dispersion in oil, 17.0 mmol). The cooling bath wasremoved and the reaction mixture was stirred at room temperature for 40minutes. The reaction was quenched by addition of saturated aqueousammonium chloride solution (4 ml) and concentrated under reducedpressure to give an orange residue. This material was partitionedbetween ethyl acetate (200 ml) and water (200 ml). The organic componentwas washed with water (100 ml), brine (75 ml) and then dried overmagnesium sulphate before being concentrated under reduced pressure. Thecrude product mixture was purified by flash chromatography on silica geleluting with dichloromethane:methanol (100:0, 99:1, then 98:2, byvolume) to provide the title compound (2.67 g) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ=1.15 (t, 3H), 1.19 (t, 3H), 2.43 (q, 2H),2.72 (s, 3H), 3.85 (q, 2H), 7.38 (s, 2H), 7.61 (s, 1H).

LRMS (electrospray): m/z 331 [M+Na⁺].

Preparation 1025-{[1-Acetyl-3-(1-bromoethyl)-5-ethyl-1H-pyrazol-4-yl]oxy}isophthalonitrile

A solution of the pyrazole from Preparation 101 (881 mg, 2.86 mmol) incarbontetrachloride (12 ml) was degassed by passing a stream of nitrogenthrough the solution for 20 minutes. N-bromosuccinimide (763 mg, 4.28mmol) was added followed by AIBN (30 mg) and the reaction mixture washeated at 85° C. for 4 hours. After cooling to room temperature themixture was concentrated under reduced pressure and the residue waspurified by flash chromatography on silica gel eluting withpentane:ethyl acetate (a gradient from 100:0 to 67:33, by volume) toprovide the title compound (348 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.10 (t, 3H), 2.00 (d, 3H), 2.70 (s, 3H),2.80 (m, 2H), 4.95 (q, 1H), 7.42 (s, 2H), 7.60 (s, 1H).

LRMS (electrospray): m/z 283 [MH⁺].

Preparation 1035-({5-Ethyl-3-(1-hydroxyethyl)-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}oxy)isophthalonitrile

To a stirred solution of the pyrazole from Example 263 (197 mg, 0.70mmol) in dimethylformamide (3 ml) at 0° C. was added2-(2-bromoethoxy)tetrahydro-2H-pyran (105 μl, 0.70 mmol) followed bysodium hydride (31 mg, 0.77 mmol). After 15 minutes the cooling bath wasremoved and the mixture was stirred at room temperature for 60 hours.The reaction mixture was quenched by addition of saturated aqueousammonium chloride solution (0.5 ml) and then concentrated under reducedpressure. The crude product mixture was purified by flash chromatographyon silica gel eluting with dichloromethane:methanol (a gradient from100:0 to 95:5, by volume) to provide the title compound (84 mg) as awhite foam which reverts to an oil on standing.

¹H NMR (400 MHz, CDCl₃): δ=1.11 (t, 3H), 1.45 (d, 3H), 1.65 (m, 6H),2.59 (q, 2H), 3.50 (m, 1H), 3.70 (m, 1H), 3.81 (m, 1H), 4.11 (m, 1H),4.25 (t, 2H), 4.56 (m, 1H), 4.76 (m, 1H), 7.40 (s, 2H), 7.55 (s, 1H).

LRMS (electrospray): m/z 411 [MH⁺].

Preparation 1043-Cyano-5-[(3,5-diethyl-1-{2-[(2-methoxyethoxy)methoxy]ethyl}-1H-pyrazol-4-yl)oxy]-N-hydroxybenzenecarboximidamide

To a stirred solution of the pyrazole from Example 261 (1.5 g, 3.76mmol) in ethanol (7.5 ml) was added a solution of sodium carbonate (200mg, 1.88 mmol) and hydroxylamine hydrochloride (262 mg, 3.76 mmol) inwater (7.5 ml). After stirring for 5 hours at room temperature thereaction mixture was concentrated under reduced pressure and the residuewas partitioned between dichloromethane (50 ml) and water (40 ml). Theaqueous phase was separated and extracted with dichloromethane (30 ml).The organic components were combined, dried over magnesium sulphate andconcentrated under reduced pressure. The crude product mixture waspurified by flash chromatography on silica gel eluting withdichloromethane:methanol (a gradient from 100:0 to 96:4, by volume) toprovide the title compound (1.13 mg) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.11 (m, 6H), 2.42 (q, 2H), 2.58 (q, 2H),3.41 (s, 3H), 3.59 (m, 4H), 3.95 (t, 2H), 4.17 (t, 2H), 4.61 (s, 2H),4.77 (broad s, 2H), 7.38 (m, 1H), 7.49 (m, 2H).

LRMS (electrospray): m/z 432 [MH⁺].

Microanalysis: Found C, 57.50; H, 6.71; N, 16.01. C₂₁H₂₆N₄O₄+0.4H₂Orequires C, 57.50; H. 6.85; N, 15.96%.

Preparation 1053-[(3,5-Diethyl-1-{2-[(2-methoxyethoxy)methoxy]ethyl}-1H-pyrazol-4-yl)oxy]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzonitrile

To a stirred solution of the amidoxime from Preparation 104 (300 mg,0.70 mmol) in pyridine (3 ml) was added trifluoroacetic anhydride (118μl, 0.83 mmol). After stirring at room temperature for 2 hours thereaction mixture was heated at 110° C. for 18 hours. After cooling toroom temperature the mixture was concentrated under reduced pressure andthe residue was partitioned between 2M aqueous HCl solution (6 ml) anddichloromethane (6 ml). The organic phase was separated and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane:methanol (a gradient from100:0 to 90:10, by volume) to provide the title compound (259 mg) as acolourless oil.

¹H NMR (400 MHz, CDCl₃): δ=1.14 (m, 6H), 2.46 (q, 2H), 2.59 (q, 2H),3.39 (s, 3H), 3.53 (q, 2H), 3.59 (q, 2H), 3.95 (q, 2H), 4.29 (q, 2H),4.68 (s, 2H), 7.34 (s, 1H), 7.87 (s, 1H), 8.04 (s, 1H).

LRMS (APCI): m/z 532 (MH⁺)

Preparations 106-108

The preparation of the following tabulated Preparations of the generalformula

were performed by a similar method to that of Preparation 105 using theappropriate acid chloride as the acylating agent in place oftrifluoroacetic anhydride.

Preparation no. R Analytical Data 106 Me ¹H NMR (400 MHz, CDCl₃): δ =1.14 (m, 6H), 2.46 (q, 2H), 2.59 (q, 2H), 2.67 (s, 3H), 3.39 (s, 3H),3.55 (q, 2H), 3.59 (q, 2H), 3.95 (q, 2H), 4.22 (q, 2H), 4.68 (s, 2H),7.27 (s, 1H), 7.82 (s, 1H), 8.00 (s, 1H). LRMS (electrospray): m/z 478[M + Na⁺] Microanalysis: Found C, 59.91; H, 6.27; N, 15.38. C₂₃H₂₉N₅O₅ +0.3H₂O requires C, 59.94; H, 6.475; N, 15.19%. 107 Et ¹H NMR (400 MHz,CDCl₃): δ = 1.14 (m, 6H), 1.44 (t, 3H), 2.42 (q, 2H), 2.48 (q, 2H), 2.98(q, 2H), 3.39 (s, 3H), 3.53 (q, 2H), 3.59 (q, 2H), 3.95 (q, 2H), 4.20(q, 2H), 4.48 (s, 2H), 7.30 (s, 1H), 7.84 (s, 1H), 8.01 (s, 1H). LRMS(electrospray): m/z 492 (M + Na⁺) 108 ^(i)Pr ¹H NMR (400 MHz, CDCl₃): δ= 1.11 (m, 6H), 1.49 (d, 6H), 2.44 (q, 2H), 2.49 (q, 2H), 3.30 (sept,1H), 3.39 (s, 3H), 3.54 (m, 2H), 3.59 (m, 2H), 3.95 (t, 2H), 4.23 (t,2H), 4.91 (s, 2H), 7.22 (m, 1H), 7.83 (m, 1H), 8.02 (m, 1H). LRMS(electrospray): m/z 506 (M + Na⁺) Microanalysis: Found C, 61.87; H,6.76; N, 14.62. C₂₅H₃₃N₅O₅ requires C, 62.10; H, 6.88; N, 14.48%.

Preparation 109 Ethyl 5-{[(tert-butoxycarbonyl)amino]methyl}nicotinate

To a stirred solution of ethyl-5-cyanonicotinate (3.0 g, 17.0 mmol;Annalen Der Chemie, 1959, 621, 106-136) in ethanol (200 ml) was addedconcentrated hydrochloric acid (3.4 ml) followed by 5% palladium oncarbon (300 mg). The reaction mixture was stirred at room temperatureunder an hydrogen atmosphere (50 psi) for 18 hours. The reaction mixturewas filtered through Arbocel® and concentrated under reduced pressure.The crude product mixture was purified by flash chromatography on silicagel eluting with dichloromethane:methanol:0.880 ammonia (a gradient from95:5:0.5 to 85:5:1.5, by volume) to provide the intermediate amine (2.1g) as a yellow oily solid. This material (2.1 g, 11.7 mmol) wassuspended in dichloromethane (22 ml) to which was added triethylamine(1.8 ml, 13.0 mmol) followed by di-tert-butyl dicarbonate (2.84 g, 13mmol). After 48 hours the reaction mixture was diluted withdichloromethane (50 ml) and washed with water (50 ml). The organiccomponent was dried over magnesium sulphate and concentrated underreduced pressure before being purified by flash chromatography on silicagel eluting with dichloromethane:methanol:0.88 ammonia (a gradient from100:0:0 to 95:5:0.5, by volume) to provide the title compound (2.0 g) asa yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=1.40 (m, 12H), 4.42 (m, 4H), 8.22 (s, 1H),8.71 (s, 1H), 9.12 (s, 1H).

LRMS (APCI): m/z 279 (M-H⁺)

Preparation 110 5-{[(tert-Butoxycarbonyl)amino]methyl}nicotinic acid

To a stirred solution of the ester from Preparation 109 (2.00 g, 7.10mmol) in 1M aqueous sodium hydroxide solution (15 ml, 15 mmol) was addedmethanol (15 ml). The reaction mixture was stirred at room temperaturefor 18 hours, after which time the methanol was removed under reducedpressure. The aqueous solution was washed with diethyl ether (2×25 ml),cooled to 0° C. and neutralised to pH7 by addition of 2M aqueoushydrochloric acid solution (7.5 ml). The mixture was concentrated underreduced pressure to give a yellow oil (1.5 g).

¹H NMR (400 MHz, (CD₃)₂SO): δ=1.37 (s, 9H), 4.16 (d, 2H), 7.51 (m, 1H),8.07 (s, 1H), 8.50 (s, 1H), 8.88 (s, 1H).

LRMS (APCI): m/z 251 (M-H⁺)

Preparation 111 5-(Aminomethyl)nicotinamide

To a stirred solution of the acid from Preparation 110 (770 mg, 3.10mmol) in dimethylformamide (15 ml) was added carbonyldiimidazole (600mg, 3.70 mmol). After 10 minutes 0.880 ammonia (1 ml) was added. After afurther 1 hour the reaction mixture was concentrated under reducedpressure and the residue was purified by flash chromatography on silicagel eluting with dichloromethane:methanol:0.88 ammonia (a gradient from95:5:0.5 to 80:20:1, by volume) to provide the boc-protectedintermediate. To a stirred solution of this material in dichloromethane(20 ml) was added trifluoroacetic acid (6 ml). After 18 hours a secondportion of trifluoroacetic acid (6 ml) was added and the reactionmixture was stirred at room temperature for 24 hours. The solution wasconcentrated under reduced pressure to give an oily residue which waspurified by flash chromatography on silica gel eluting withdichloromethane:methanol:0.88 ammonia (100:0:0 then 90:10:1 then80:20:1, by volume) to provide the title compound (650 mg) as a yellowoil.

¹H NMR (400 MHz, (CD₃)₂SO): δ=4.11 (s, 2H), 7.5 (broad s), 7.59 (broads), 8.14 (broad s), 8.31 (m, 1H), 8.72 (m, 1H), 8.90 (m, 1H).

LRMS (electrospray): m/z 152 (MH⁺)

HRMS: [MH⁺] 152.0819. C₇H₁₀N₃O requires 152.0818

Preparation 112 Ethyl2-{[(tert-butoxycarbonyl)amino]methyl}isonicotinate

To a stirred solution of ethyl 2-cyanoisonicotinate (2.00 g, 11.0 mmol,J. Med. Chem., 1976, 19, 483) in ethanol (20 ml) was added 2M aqueoushydrochloric acid solution (7.5 ml) followed by 5% palladium on carbon(200 mg). The reaction mixture was stirred at room temperature under ahydrogen atmosphere (60 psi) for 48 hours. The mixture was filteredthrough arbocel and the filtrate was concentrated under reducedpressure. The residue was dried by azeotropic distillation using tolueneunder reduced pressure. To a stirred solution of the residue (3.00 g) indichloromethane (22 ml) was added triethylamine (4.6 ml, 33 mmol)followed by di-tert-butyl dicarbonate (2.62 g, 12.0 mmol). Afterstirring for 1 hour at room temperature the reaction mixture was dilutedwith dichloromethane (100 ml) and washed with water (50 ml). The organiccomponent was washed with brine (50 ml), dried over magnesium sulphateand concentrated under reduced pressure to give a brown oily solid. Thecrude product mixture was purified by flash chromatography on silica geleluting with dichloromethane:methanol:0.88 ammonia (98:2:0.2 then97:3:0.3, by volume) to provide the title compound (2.20 g) as a yellowoil.

¹H NMR (400 MHz, CDCl₃): δ=1.38 (t, 3H), 1.45 (s, 9H), 4.38 (q, 2H),4.50 (m, 2H), 5.50 (broad s, 1H), 7.73 (d, 1H), 7.81 (s, 1H), 8.65 (d,1H).

LRMS (electrospray): m/z 281 (MH⁺)

Preparation 113 2-{[(tert-Butoxycarbonyl)amino]methyl}isonicotinic acid

To a stirred solution of the ester from Preparation 112 (1.50 g, 5.35mmol) in methanol (10 ml) was added 1M aqueous sodium hydroxide solution(10 ml). After 1 hour the reaction mixture was cooled to 0° C. andneutralised by addition of 2M aqueous hydrochloric acid solution (5 ml).The reaction mixture was concentrated under reduced pressure and theresidue was purified by flash chromatography on silica gel eluting withdichloromethane:methanol:0.880 ammonia (80:20:1, by volume) to providethe title compound (1.30 g) as a yellow foam.

¹H NMR (400 MHz, (CD₃OD): δ=1.43 (s, 9H), 4.36, (s, 2H), 7.68 (m, 1H),7.81 (s, 1H), 8.47 (m, 1H).

LRMS (electrospray): m/z 251 (M-H⁺)

HRMS: [MH⁺] 253.1179. C₁₂H₁₇N₂O4 requires 253.1183

Preparation 114 tert-Butyl[4-(aminocarbonyl)-2-pyridinyl]methylcarbamate

To a stirred solution of the acid from Preparation 113 (1.3 g, 5.20mmol) in dimethylformamide (10 ml) was added 1-hydroxybenzotriazole (950mg, 6.20 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride salt (1.20 g, 6.20 mmol). After 1 hour 0.880 ammonia (5ml) was added and the reaction mixture was stirred at room temperaturefor 1.5 hours. The mixture was concentrated under reduced pressure anddried by azeotropic distillation using toluene under reduced pressure togive a yellow semi-solid. The crude product mixture was purified byflash chromatography on silica gel eluting withdichloromethane:methanol:0.88 ammonia (95:5:0.5, by volume) to providethe title compound (1.1 g) as a clear oil which crystallised onstanding. This material was further purified by triturating with diethylether (10 ml) which gave a sample of the desired product (1.0 g) whitepowder/

¹H NMR (400 MHz, D6-DMSO): δ=1.39 (s, 9H), 4.25 (m, 2H), 7.44 (m, 1H),7.61 (m, 1H), 7.66 (broad s, 2H), 8.21 (broad s, 1H), 8.59 (d, 1H).

LRMS (electrospray): m/z 250 (M-H⁺)

Microanalysis: Found C, 57.26; H. 6.86; N, 16.65. C₁₂H₁₇N₃O₃ requires C,57.36; H, 6.82; N, 16.72%.

Preparation 115 2-(Aminomethyl)isonicotinamide

To a stirred solution of the pyridine from Preparation 114 (1.00 g, 3.98mmol) in dichloromethane (50 ml) was added trifluoroacetic acid (15 ml).After stirring at room temperature for 18 hours the reaction mixture wasconcentrated under reduced pressure and purified by ion-exchangechromatography on Dowex 50-X8-200 eluting with water followed by 0.880ammonia:methanol:water (5:5:90, by volume) to provide the title compound(265 mg) as a white solid.

¹H NMR (400 MHz, D6-DMSO): δ=2.1 (broad s, 1H), 3.4 (broad s, 1H), 3.85(2H, s), 7.57 (m, 1H), 7.60 (broad s, 1H), 7.80 (m, 1H), 8.16 (broad s,1H), 8.59 (m, 1H).

LRMS (APCI): m/z 152 (MH⁺)

1. A method of treating an HIV-1 infection in a mammal, which comprisessimultaneous or sequential administration of a compound of formula (I),

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ isH, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl, benzyl, halo, —CN, —OR⁷,—CO₂R¹⁰, —CONR⁵R¹⁰, R⁸ or R⁹, said C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyland benzyl being optionally substituted by halo, —CN, —OR¹⁰,S(O)_(x)R¹⁰, —CO₂R¹⁰, —CONR⁵R¹⁰, —OCONR⁵R¹⁰; —NR⁵CO₂R¹⁰, —NR¹⁰R¹¹,—NR⁵COR¹⁰, —SO₂NR⁵R¹⁰, —NR⁵CONR⁵R¹⁰, —NR⁵SO₂R¹⁰ or R¹⁰; and R² is H,C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkenyl, phenyl, benzyl, R⁸ or R⁹, said C₁-C₆ alkyl, C₃-C₇cycloalkyl, phenyl and benzyl being optionally substituted by halo,—OR⁵, OR¹², —CN, —CO₂R⁷, —OCONR⁵R⁵, —CONR⁵R⁵, —C(═NR⁵)NR⁵OR⁵,—CONR⁵NR⁵R⁵, —NR⁶R⁶, —NR⁵R¹², —NR⁵COR⁵, —NR⁵COR⁸, —NR⁵COR¹², —NR⁵CO₂R⁵,—NR⁵CONR⁵R⁵, —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —NR⁵SO₂NR⁵R⁵, R⁸ or R⁹; R³ is H,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl, benzyl, halo, —CN, —OR⁷, —CO₂R⁵,—CONR⁵R⁵, R⁸ or R⁹, said C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl andbenzyl being optionally substituted by halo, —CN, —OR⁵, —CO₂R⁵,—CONR⁵R⁵, —OCONR⁵R⁵, —NR⁵CO₂R⁵, —NR⁶R⁶, —NR⁵COR⁵, —SO₂NR⁵R⁵,—NR⁵CONR⁵R⁵, —NR⁵SO₂R⁵, R⁸ or R⁹; R⁴ is phenyl or naphthyl, each beingoptionally substituted by R⁸, halo, —CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, —CONR⁵R⁵, OR¹³, SO_(X)R⁶, O—(C₁-C₆alkylene)-CONR⁵R⁵, O—(C₁-C₆ alkylene)-NR⁵R⁵, or O—(C₁-C₆ alkylene)-OR⁶;each R⁵ is independently either H, C₁-C₆ alkyl or C₃-C₇ cycloalkyl or,when two R⁵ groups are attached to the same nitrogen atom, those twogroups taken together with the nitrogen atom to which they are attachedrepresent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyland morpholinyl being optionally substituted by C₁-C₆ alkyl or C₃-C₇cycloalkyl; each R⁶ is independently either H, C₁-C₆ alkyl or C₃-C₇cycloalkyl; R⁷ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl; R⁸ is a five orsix-membered, aromatic heterocyclic group containing (i) from 1 to 4nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphurheteroatom(s), said heterocyclic group being optionally substituted byhalo, oxo, —CN, —COR⁵, —CONR⁵R⁵, —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —OR⁵, —NR⁵R⁵,—(C₁-C₆ alkylene)-NR⁵R⁵, C₁-C₆ alkyl, fluoro(C₁-C₆)alkyl or C₃-C₇cycloalkyl; R⁹ is a four to seven-membered, saturated or partiallyunsaturated heterocyclic group containing (i) 1 or 2 nitrogenheteroatom(s) or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulphurheteroatom or (iii) 1 oxygen or sulphur heteroatom, said heterocyclicgroup being optionally substituted by oxo, C₁-C₆ alkyl, C₃-C₇cycloalkyl, —SO₂R⁵, —CONR⁵R⁵, —COOR⁵, —CO—(C₁-C₆ alkylene)-OR⁵ or —COR⁵and optionally substituted on a carbon atom which is not adjacent to aheteroatom by halo, —OR, —NR⁵R⁵, —NR⁵COR⁵, —NR⁵COOR⁵, —NR⁵CONR⁵R⁵,—NR⁵SO₂R⁵ or —CN; R¹⁰ is H, R⁸, R⁹, R¹³, C₁-C₆ alkyl, C₃-C₇ cycloalkylor —(C₁-C₆ alkyl)-(C₃-C₇ cycloalkyl), said C₁-C₆ alkyl and C₃-C₇cycloalkyl being optionally substituted by —OR⁵, —OR¹³, R⁸, R⁹, R¹³ or—COR¹³; R¹¹ is H, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, said C₁-C₆ alkyl andC₃-C₇ cycloalkyl being optionally substituted by —OR⁵, —NR⁵R⁵, —NR⁵COR⁵,—CONR⁵R⁵, R⁸ or R⁹; R¹² is C₁-C₆ alkyl substituted by R⁸, R⁹, —OR⁵,—CONR⁵R⁵, —NR⁵COR⁵ or —NR⁵R⁵; R¹³ is phenyl optionally substituted byhalo, —CN, —COR⁵, —CONR⁵R⁵, —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —OR⁵, —NR⁵R⁵, —(C₁-C₆alkylene)-NR⁵R⁵, C₁-C₆ alkyl, halo(C₁-C₆)alkyl or C₃-C₇ cycloalkyl; andx is 0, 1 or 2; with one or more additional therapeutic agents.
 2. Themethod of claim 1 wherein R¹ is H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl or—OR⁷, said C₁-C₆ alkyl being optionally substituted by halo, —OR¹⁰,—NR¹⁰R¹¹, —NR⁵COR¹⁰ or R¹⁰.
 3. The method of claim 1 wherein R² is H,C₁-C₆ alkyl, C₃-C₆ alkenyl or R⁹, said C₁-C₆ alkyl being optionallysubstituted by —OR⁵, —OR¹², —CN, —CO₂R⁷, —CONR⁵R⁵, —C(═NR⁵)NR⁵OR⁵,—CONR⁵NR⁵R⁵, —NR⁶R⁶, —NR⁵R¹², —NR⁵COR⁸, —NR⁵COR¹², —NR⁵CO₂R⁵, R⁸ or R⁹.4. The method of claim 1 wherein R³ is H or C₁-C₆ alkyl.
 5. The methodof claim 1 wherein R⁴ is phenyl substituted by halo, —CN or C₁-C₆ alkyl.6. The method of claim 1 wherein the compound of formula (I) is5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrileor a pharmaceutically acceptable salt or solvate thereof.
 7. The methodof claim 1 wherein the compound of formula (I) is5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrileor a pharmaceutically acceptable salt thereof.
 8. The method of claim 1wherein the compound of formula (I) is5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile.9. The method of claim 1 wherein the one or more additional therapeuticagents are (a) one or more reverse transcriptase inhibitors comprisingzidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir andadefovir; (b) one or more non-nucleoside reverse transcriptaseinhibitors comprising nevirapine, delavirdine and efavirenz; (c) one ormore HIV protease inhibitors comprising indanivir, ritonavir, saquinavirand nelfinavir; (d) one or more CCR5 antagonists comprising TAK-779; (e)one or more CXCR4 antagonists such comprising AMD-3100; (f) one or moreintegrase inhibitors; (g) one or more inhibitors of viral fusioncomprising T-20; (h) one or more investigational drugs comprisingtrizivir, KNI-272, amprenavir, GW-33908, FTC, PMPA, S-1153, MKC-442,MSC-204, MSH-204, MSH-372, DMP450, PNU-140690, ABT-378, KNI-764,DPC-083, TMC-120 or TMC-125; or (i) one or more antifungal orantibacterial agents comprising fluconazole.
 10. The method of claim 1wherein the one or more additional therapeutic agents are FTC and PMPA.11. The method of claim 6 wherein the one or more additional therapeuticagents are FTC and PMPA.
 12. A pharmaceutical composition comprising acompound of the formula (I),

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ isH, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl, benzyl, halo, —CN, —OR⁷,—CO₂R¹⁰, —CONR⁵R¹⁰, R⁸ or R⁹, said C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyland benzyl being optionally substituted by halo, —CN, —OR¹⁰,S(O)_(x)R¹⁰, —CO₂R¹⁰, —CONR⁵R¹⁰, —OCONR⁵R¹⁰, —NR⁵CO₂R¹⁰, —NR¹⁰R¹¹,—NR⁵COR¹⁰, —SO₂NR⁵R¹⁰, —NR⁵CONR⁵R¹⁰, —NR⁵SO₂R¹⁰ or R¹⁰; and R² is H,C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkenyl, phenyl, benzyl, R⁸ or R⁹, said C₁-C₆ alkyl, C₃-C₇cycloalkyl, phenyl and benzyl being optionally substituted by halo,—OR⁵, —OR¹², —CN, —CO₂R⁷, —OCONR⁵R⁵, —CONR⁵R⁵, —C(═NR⁵)NR⁵OR⁵,—CONR⁵NR⁵R⁵, —NR⁶R⁶, —NR⁵R¹², —NR⁵COR⁵, —NR⁵COR⁸, —NR⁵COR¹², —NR⁵CO₂R⁵,—NR⁵CONR⁵R⁵, —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —NR⁵SO₂NR⁵R⁵, R⁸ or R⁹; R³ is H,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl, benzyl, halo, —CN, —OR⁷, —CO₂R⁵,—CONR⁵R⁵, R⁸ or R⁹, said C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl andbenzyl being optionally substituted by halo, —CN, —OR⁵, —CO₂R⁵,—CONR⁵R⁵, —OCONR⁵R⁵, —NR⁵CO₂R⁵, —NR⁶R⁶, —NR⁵COR⁵, —SO₂NR⁵R⁵,—NR⁵CONR⁵R⁵, —NR⁵SO₂R⁵, R⁸ or R⁹; R⁴ is phenyl or naphthyl, each beingoptionally substituted by R⁸, halo, —CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, —CONR⁵R⁵, OR¹³, SO_(X)R⁶, O—(C₁-C₆alkylene)-CONR⁵R⁵, O—(C₁-C₆ alkylene)-NR⁵R⁵, or O—(C₁-C₆ alkylene)-OR⁶;each R⁵ is independently either H, C₁-C₆ alkyl or C₃-C₇ cycloalkyl or,when two R⁵ groups are attached to the same nitrogen atom, those twogroups taken together with the nitrogen atom to which they are attachedrepresent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyland morpholinyl being optionally substituted by C₁-C₆ alkyl or C₃-C₇cycloalkyl; each R⁶ is independently either H, C₁-C₆ alkyl or C₃-C₇cycloalkyl; R⁷ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl; R⁸ is a five orsix-membered, aromatic heterocyclic group containing (i) from 1 to 4nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphurheteroatom(s), said heterocyclic group being optionally substituted byhalo, oxo, —CN, —COR⁵, —CONR⁵R⁵, —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —OR^(S), —NR⁵R⁵,—(C₁-C₆ alkylene)-NR⁵R⁵, C₁-C₆ alkyl, fluoro(C₁-C₆)alkyl or C₃-C₇cycloalkyl; R⁹ is a four to seven-membered, saturated or partiallyunsaturated heterocyclic group containing (i) 1 or 2 nitrogenheteroatom(s) or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulphurheteroatom or (iii) 1 oxygen or sulphur heteroatom, said heterocyclicgroup being optionally substituted by oxo, C₁-C₆ alkyl, C₃-C₇cycloalkyl, —SO₂R⁵, —CONR⁵R⁵, —COOR⁵, —CO—(C₁-C₆ alkylene)-OR⁵ or —COR⁵and optionally substituted on a carbon atom which is not adjacent to aheteroatom by halo, —OR⁵, —NR⁵R⁵, —NR⁵COR⁵, —NR⁵COOR⁵, —NR⁵CONR⁵R⁵,—NR⁵SO₂R⁵ or —CN; R¹⁰ is H, R⁸, R⁹, R¹³, C₁-C₆ alkyl, C₃-C₇ cycloalkylor —(C₁-C₆ alkyl)-(C₃-C₇ cycloalkyl), said C₁-C₆ alkyl and C₃-C₇cycloalkyl being optionally substituted by —OR⁵, —OR¹³, R⁸, R⁹, R¹³ or—COR¹³; R¹¹ is H, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, said C₁-C₆ alkyl andC₃-C₇ cycloalkyl being optionally substituted by —OR⁵, —NR⁵R⁵, —NR⁵COR⁵,—CONR⁵R⁵, R⁸ or R⁹; R¹² is C₁-C₆ alkyl substituted by R⁸, R⁹, —OR⁵,—CONR⁵R⁵, —NR⁵COR⁵ or —NR⁵R⁵; R¹³ is phenyl optionally substituted byhalo, —CN, —COR⁵, —CONR⁵R⁵, —SO₂NR⁵R⁵, —NR⁵SO₂R⁵, —OR⁵, —NR⁵R⁵, —(C₁-C₆alkylene)-NR⁵R⁵, C₁-C₆ alkyl, halo(C₁-C₆)alkyl or C₃-C₇ cycloalkyl; andx is 0, 1 or 2; and one or more additional therapeutic agents, togetherwith one or more pharmaceutically acceptable excipients, diluents orcarriers.
 13. The pharmaceutical composition of claim 12 wherein R¹ isH, C₁-C₆ alkyl, C₃-C₇ cycloalkyl or —OR⁷, said C₁-C₆ alkyl beingoptionally substituted by halo, —OR¹⁰, —NR¹⁰R¹¹, —NR⁵COR¹⁰ or R¹⁰. 14.The pharmaceutical composition of claim 12 wherein R² is H, C₁-C₆ alkyl,C₃-C₆ alkenyl or R⁹, said C₁-C₆ alkyl being optionally substituted by—OR⁵, —OR¹², —CN, —CO₂R⁷, —CONR⁵R⁵, —C(═NR⁵)NR⁵OR⁵, —CONR⁵NR⁵R⁵, —NR⁶R⁶,—NR⁵R¹², —NR⁵COR⁸, —NR⁵COR¹², —NR⁵CO₂R⁵, R⁸ or R⁹.
 15. Thepharmaceutical composition of claim 12 wherein R³ is H or C₁-C₆ alkyl.16. The pharmaceutical composition of claim 12 wherein R⁴ is phenylsubstituted by halo, —CN or C₁-C₆ alkyl.
 17. The pharmaceuticalcomposition of claim 12 wherein the compound of formula (I) is5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrileor a pharmaceutically acceptable salt or solvate thereof.
 18. Thepharmaceutical composition of claim 12 wherein the compound of formula(I) is5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrileor a pharmaceutically acceptable salt thereof.
 19. The pharmaceuticalcomposition of claim 12 wherein the compound of formula (I) is5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile.20. The pharmaceutical composition of claim 12 wherein the one or moreadditional therapeutic agents are (a) one or more reverse transcriptaseinhibitors comprising zidovudine, didanosine, zalcitabine, stavudine,lamivudine, abacavir and adefovir; (b) one or more non-nucleosidereverse transcriptase inhibitors comprising nevirapine, delavirdine andefavirenz; (c) one or more HIV protease inhibitors comprising indanivir,ritonavir, saquinavir and nelfinavir; (d) one or more CCR5 antagonistscomprising TAK-779; (e) one or more CXCR4 antagonists comprisingAMD-3100; (f) one or more integrase inhibitors; (g) one or moreinhibitors of viral fusion comprising T-20; (h) one or moreinvestigational drugs comprising trizivir, KNI-272, amprenavir,GW-33908, FTC, PMPA, S-1153, MKC-442, MSC-204, MSH-204, MSH-372, DMP450,PNU-140690, ABT-378, KNI-764, DPC-083, TMC-120 or TMC-125; or (i) one ormore antifungal or antibacterial agents comprising fluconazole.
 21. Thepharmaceutical composition of claim 12 wherein the one or moreadditional therapeutic agents are FTC and PMPA.
 22. The pharmaceuticalcomposition of claim 17 wherein the one or more additional therapeuticagents are FTC and PMPA.
 23. The method of claim 1 wherein the one ormore additional therapeutic agents are lamivudine and abacavir.
 24. Themethod of claim 6 wherein the one or more additional therapeutic agentsare lamivudine and abacavir.
 25. The pharmaceutical composition of claim12 wherein the one or more additional therapeutic agents are lamivudineand abacavir.
 26. The pharmaceutical composition of claim 17 wherein theone or more additional therapeutic agents are lamivudine and abacavir.